CN101048139A - Compositions for controlled delivery of pharmaceutically active compounds - Google Patents
Compositions for controlled delivery of pharmaceutically active compounds Download PDFInfo
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- CN101048139A CN101048139A CNA2005800366905A CN200580036690A CN101048139A CN 101048139 A CN101048139 A CN 101048139A CN A2005800366905 A CNA2005800366905 A CN A2005800366905A CN 200580036690 A CN200580036690 A CN 200580036690A CN 101048139 A CN101048139 A CN 101048139A
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- pharmaceutical composition
- acid
- amino
- active compounds
- reactive compound
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to pharmaceutical compositions that provide sustainedrelease of a pharmaceutically active compound and to methods of treating or preventing a condition in an animal by administering the pharmaceutical compositions to the animal by injection. When the pharmaceutical compositions are administered to an animal by injection, they form a drug depot that releases the pharmaceutically active compound over time. The pharmaceutical compositions can also be administered orally.
Description
1. invention field
The present invention relates to continue the release medicinal compositions, and give the method for animal pharmaceuticals reactive compound with this type of lasting release medicinal compositions.
2. background of invention
With controlled release or the slow releasing preparation administration that can keep the treatment blood level in the time that prolongs often is ideal.These controlled release preparations have reduced administration frequency, thereby have improved convenience and compliance, have also reduced the seriousness and the occurrence frequency of side effect.By the blood level of keeping substantial constant and the fluctuation of avoiding blood level, for example with the administration every day relevant fluctuation of conventional immediate release formulations several times, controlled release or slow releasing preparation can provide the better treatment curve that obtains than available conventional immediate release formulations.
Known control drug release or the method that medicine continue to be discharged comprise for example osmotic pumps of implanting device, but and be dispersed in medicine in the bioavailable polymer skeleton, this medicine is implantable, oral administration or injection.But the bioavailable polymer example that is used for this type of application comprises poly-(lactic acid) and lactic acid-ethanol copolymer.This polymer experiences hydrolysis slowly usually in vivo, constantly discharges the medicine that is wrapped up in time.Polymer degradation products is nontoxic and can be absorbed or metabolism by health.For example, but when bioavailable polymer was poly-(lactic acid) or lactic acid-ethanol copolymer, catabolite was parent acid, lactic acid and glycolic, and these acid can be absorbed by health.
U.S. Patent number 6,887,487 and 6,946,137 disclose the compositions of salt and the lipotropy counter ion counterionsl gegenions and the pharmaceutically acceptable water-soluble solvent of pharmaceutical active compounds, and these components mix provides composition for injection.In the time of in being expelled to animal body, the part of said composition is separated out the storage storehouse that formation slowly discharges pharmaceutical active compounds in time at least.
Application No. US 2004/0220264 discloses the compositions that comprises the molecular complex between acidic drug and the functional substance, the purposes for preparing the method and composition of said composition.This functional substance can be basic amino acid, amino acid amide, amino-acid ester or related amino acid.Allegedly compositions can be used for drug release to skin histology.
Application No. US 2004/0197408 discloses the diblock copolymer with hydrophobicity block and hydrophilic block, the preparation that is selected from amino acid whose additive and oligopeptide.When mixing with water, this type of preparation forms the drug release carrier of micelle form.
Yet, in the art the medicine that contains Pharmaceutical composition being still had demand, it is applicable to injection or implants that wherein said preparation provides controlled delivery of pharmaceutical agents to discharge or continues and discharges.
The quoting of any list of references in the application's the 5th part should not be interpreted into the prior art that this list of references is the application.
3. summary of the invention
The present invention relates to Pharmaceutical composition, this Pharmaceutical composition comprises (i) amino-acid ester or amino acid amide, (ii) acidic drug reactive compound, and (iii) pharmaceutically acceptable organic solvent, wherein this Pharmaceutical composition is injectable and forms precipitation when the injection entry.In one embodiment, Pharmaceutical composition comprises amino-acid ester.In one embodiment, Pharmaceutical composition comprises amino acid amide.
The invention still further relates to Pharmaceutical composition, said composition comprises (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, and (iv) pharmaceutically acceptable organic solvent, wherein this Pharmaceutical composition is injectable and forms precipitation when the injection entry.In one embodiment, Pharmaceutical composition comprises amino-acid ester.In one embodiment, Pharmaceutical composition comprises amino acid amide.
The invention still further relates to Pharmaceutical composition, said composition comprises (i) N-acylamino acid, (ii) alkalescent medicine reactive compound, and (iii) pharmaceutically acceptable organic solvent, and wherein this Pharmaceutical composition is injectable and forms precipitation when the injection entry.
The invention still further relates to the method for treatment animal disease, this method comprises the animal that needs are arranged Pharmaceutical composition of the present invention.
4. accompanying drawing summary
The flunixin percentage ratio that Fig. 1 represents to be discharged in the various flunixin preparations is to time function.The flunixin percentage ratio that (▲) representative discharges from the compositions that contains flunixin and tryptophan monooctyl ester salt, (■) represent the flunixin percentage ratio that from the compositions that contains flunixin and tryptophan butyl ester salt, discharges, and (◆) represents the flunixin percentage ratio that discharges from the compositions that contains the free flunixin that is dissolved in N-Methyl pyrrolidone.
Fig. 2 represents the average flunixin serum-concentration of two dogs to the function of time, and these dogs give the Banamine that dosage is 8mg/kg
Fig. 3 represents the function of the average flunixin serum-concentration of four dogs to the time, these dogs give the present composition that dosage is 8mg/kg, said composition is pressed the description preparation among the embodiment 9.2, contains the propylene glycol and the glycerol formal solution of flunixin and tryptophan monooctyl ester salt.
5. detailed Description Of The Invention
The present invention relates to the Pharmaceutical composition of pharmaceutical active compounds administrable.This based composition provides the lasting release or the sustained release of pharmaceutical active compounds.The invention still further relates to the method for treatment animal disease, this method comprises the animal that needs are arranged Pharmaceutical composition of the present invention.
The present invention relates to Pharmaceutical composition, this Pharmaceutical composition comprises (i) amino-acid ester or amino acid amide and (ii) acidic drug reactive compound.In one embodiment, this Pharmaceutical composition comprises amino-acid ester.In one embodiment, this Pharmaceutical composition comprises amino acid amide.In one embodiment, this Pharmaceutical composition is a solid.
In one embodiment, this Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.Therefore, the invention still further relates to Pharmaceutical composition, said composition comprises (i) amino-acid ester or amino acid amide, (ii) acidic drug reactive compound, and (iii) pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition comprises amino-acid ester.In one embodiment, this Pharmaceutical composition comprises amino acid amide.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent comprises the suspension of solid particle in pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
The invention still further relates to Pharmaceutical composition, said composition comprises (i) amino-acid ester or amino acid amide, the pharmaceutically acceptable salt of (ii) carboxylic acid, and (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds.In one embodiment, this Pharmaceutical composition comprises amino-acid ester.In one embodiment, this Pharmaceutical composition comprises amino acid amide.In one embodiment, this Pharmaceutical composition is a solid.
In one embodiment, this Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.Therefore, the invention still further relates to Pharmaceutical composition, said composition comprises (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, and (iv) pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition comprises amino-acid ester.In one embodiment, this Pharmaceutical composition comprises amino acid amide.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent comprises the suspension of solid particle in pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
The invention still further relates to Pharmaceutical composition, said composition comprises (i) N-acylamino acid and (ii) alkalescent medicine reactive compound.In one embodiment, this Pharmaceutical composition is a solid.
In one embodiment, this Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.Therefore, the invention still further relates to Pharmaceutical composition, said composition comprises (i) N-acylamino acid, (ii) alkalescent medicine reactive compound, and (iii) pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent comprises the suspension of solid particle in pharmaceutically acceptable organic solvent.In one embodiment, this Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
5.1 definition
As using herein, following term has following implication:
" C
1-C
22Alkyl " refer to have the straight or branched of 1-22 carbon atom, saturated or unsaturated, ring-type or non-annularity, aromatics or non-aromatics, carbocyclic ring or heterocyclic radical because of.Similarly, " C
1-C
21Alkyl ", " C
1-C
18Alkyl ", " C
6-C
18Alkyl ", " C
8-C
18Alkyl " and " C
10-C
18Alkyl " refer to have 1-21 carbon atom respectively, the straight or branched of a 1-18 carbon atom, a 6-18 carbon atom, a 8-18 carbon atom and 10-18 carbon atom, saturated or unsaturated, ring-type or non-annularity, aromatics or non-aromatics, carbocyclic ring or heterocyclic group.Therefore, phrase " formula-C (O)-R
1Acyl group, R wherein
1Be C
1-C
21Group " refer to formula-C (O)-R
1Acyl group, R wherein
1Be straight or branched with 1-21 carbon atom, saturated or unsaturated, ring-type or non-annularity, aromatics or non-aromatics, carbocyclic ring or heterocycle alkyl.Representational formula-C (O)-R
1Acyl group, wherein R
1Be unsubstituted C
1-C
21Group includes but not limited to acetyl group, propiono, bytyry, caproyl (hexanoyl), caproyl (caproyl), lauroyl, myristoyl, palmityl, stearyl, palmitoleoyl (palmioleoyl), oleoyl, inferior oleoyl, Caulis et Folium Lini acyl group and benzoyl.
As using herein, term " salt " refers to not be covalent bonding, but passes through two kinds of chemical compounds of ionic interaction chemical bonding.
As using herein, term " pharmaceutically acceptable organic solvent " refers to not have for example over-drastic toxicity of unsuitable ill effect, zest or anaphylaxis when giving animal, with rational interests/risk than the organic solvent that matches.Preferably, pharmaceutically acceptable organic solvent is for to be commonly referred to be safe solvent (" GRAS ") by U.S. food and drug administration (" FDA ").
As using herein, term " organic solvent that dissolves each other with water " refers to and can mix with water and without separating into biphase organic solvent with any ratio.
As using term " water-miscible organic solvent " refers to have obvious dissolubility level in water organic solvent herein.Typically, water-miscible organic solvent is with at least about 5% weight, and preferably at least about 10% weight, more preferably at least about 20% weight, most preferably the amount at least about 50% weight is dissolved in the water.For example, glyceryl triacetate is considered to water-soluble solvent, because it dissolves with about 1: 14 ratio in water.
As using herein, phrase " forms precipitation " and refers to that Pharmaceutical composition forms precipitation or solid when injecting entry or being injected into physiology (in the body) environment.Precipitation is in room temperature, at insoluble solid external or that form in the solution in physiology (in the body) environment.Precipitation can have various ways, for example solid, crystallization, viscosity block or gel.Preferably, be precipitated as viscosity block or gel.When the present composition and water mix when being incorporated in 98 and filtering, said composition forms precipitation in water, and at least 10% compositions is trapped within on the 0.22 μ m filter at this moment.Generally, about 1mL Pharmaceutical composition is injected in about 5mL water in order to form precipitation.
As using term " fatty acid " herein " refer to the carboxylic acid of formula R-C (O) OH, wherein R is C
6-C
22Straight or branched, saturated or unsaturated alkyl.Representational fatty acid includes but not limited to caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, palmitic acid (palmic acid), oleic acid, linoleic acid plus linolenic acid.
As using herein, term " fluoroquinolone " refers to have any chemical compound of following basic structure:
R wherein
1, R
2, R
3And R
4Can be various functional groups, X can be and can be substituted or unsubstituted carbon or nitrogen.Those skilled in the art can recognize easily that fluoroquinolone can be used for the compositions and methods of the invention.Fluoroquinolone is generally as antibiotic, but they also can be used for treating other diseases (for example nephrotic syndrome).
As using herein, phrase " injectable " or " composition for injection " refer to be sucked into syringe and through subcutaneous, intraperitoneal or intramuscular injection to animal, not can because of solid matter in compositions existence and cause the compositions of untoward reaction.Solid matter includes but not limited to crystallization, viscosity block and gel.General filter by filter in 98 when preparation, be no more than 10%, preferably be no more than 5%,, and when being most preferably not exceeding 1% said preparation and being trapped within on the 0.22 μ m filter, think that preparation or compositions are injectable more preferably no more than 2%.
As using herein, term " suspension " refers to be evenly dispersed in the solid particle in the solvent, and this solvent can be aqueous or nonaqueous.In one embodiment, particulate particle mean size is less than about 100 μ m, use for example commercial can be from Microtrac Inc.ofMontgomeryville, the Particle Size Analyzer that PA. obtains is measured.
As using herein, term " animal " includes but not limited to the mankind, Canis animals, felid, equine species, bovid, caprid, porcine animals, Amphibian, reptile and birds.Representational animal includes but not limited to milch cow, horse, sheep, pig, ungulate, orangutan, monkey, baboon, chicken, turkey, mice, rabbit, rat, Cavia porcellus, Canis familiaris L., cat and people.In one embodiment, animal is a mammal.In one embodiment, animal is behaved, and in one embodiment, animal is Canis animals, felid, equine species, bovid, caprid or porcine animals.
As using herein, term " pharmaceutical active compounds " refers to produce the chemical compound of pharmacological action in animal.Pharmacological action is generally treatment or prevention animal disease.
As using herein, term " disease " refer to body function, system or organ interruption, stop or lacking of proper care.Representational disease includes but not limited to infect for example antibacterial, virus, fungus and parasitic infection; Disease is cancer for example; Inflammation; Diabetes; And organ failure.
As using herein, term " effective dose " refers to the amount of enough treatments or prevention animal disease.
Phrase " treatment ", " treatment " etc. comprise the improvement of concrete disease or stop.
Phrase " prevention ", " prevention " etc. comprise avoiding of disease outbreak.
As using herein, phrase " drug depot " refers to the precipitation that comprises pharmaceutical active compounds that forms in by the treatment animal body, and this precipitation discharges the pharmaceutical active compounds of pharmacy effective dose in time.
As using herein, phrase " neutral pharmaceutical active compounds " refers to not have the pharmaceutical active compounds of net charge.Neutral pharmaceutical active compounds comprises amphion.
As using herein, phrase " acidic drug reactive compound " refers to have acidic functionality, promptly can supply with the pharmaceutical active compounds of the group of basic functionality such as amino proton.Representational acidic functionality includes but not limited to-COOH (being carboxyl) ,-S (O)
2-OH (being sulfo group) ,-OP (O) (OR) (OH) ,-O (P) (OH)
2,-P (O) (OR) (OH) ,-(P) (OH)
2) ,-OP (O) (R) (OH) and-P (O) (R) (OH), wherein R is for can choose substituted alkyl wantonly.
As using herein, phrase " alkalescent medicine reactive compound " refers to have basic functionality, promptly can from acidic functionality for example carboxyl accept the pharmaceutical active compounds of the group of proton.Representational basic functionality is amino.
As using herein, the serve as reasons salt of basic group formation of acid and pharmaceutical active compounds of phrase " pharmaceutically acceptable salt ".Exemplary salt includes but not limited to sulfate, citrate, acetate, oxalates, hydrochlorate, bromide, iodide, nitrate, disulfate, phosphate, acid phosphate, .gamma.-pyridinecarboxylic acid salt, lactate, Salicylate, the acid citrate, tartrate, oleate, tannate, pantothenate, biatrate, Ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formates, benzoate, glutamate, Glu, mesylate, esilate, benzene sulfonate, tosilate and pamoate (promptly 1,1 '-methylene-two-(2-hydroxyl-3-naphthoate)).Term " pharmaceutically acceptable salt " also refers to by having acidic functionality, for example the salt of the pharmaceutical active compounds of carboxylic acid functional and pharmaceutically acceptable inorganic base or organic base preparation.Suitable alkali includes but not limited to for example hydroxide of sodium, potassium and lithium of alkali metal; Alkaline-earth metal is the hydroxide of calcium and magnesium for example; Other metals are the hydroxide of aluminum and zinc for example; Ammonia and organic amine, one, two or trialkylamine of for example unsubstituted or hydroxyl-replacement; Hexanamine; Tri-butylamine; Pyridine; The N-methyl amine, the N-ethylamine; Diethylamine; Triethylamine; Single-, two-or three-(2-hydroxy lower alkyl amine) for example single-, two-or three-(2-hydroxyethyl) amine, 2-hydroxyl-tert-butylamine or three-(methylol) methylamine, N, N-two-low alkyl group-N-(hydroxy lower alkyl)-amine is N for example, N-dimethyl-N-(2-ethoxy) amine, or three-(2-ethoxy) amine; N-methyl D-glycosamine; Reach aminoacid for example arginine, lysine etc.
As using herein, phrase " essentially no " refers to less than about 2% weight, preferably less than about 1% weight, is more preferably less than about 0.5% weight, and most preferably less than about 0.2% weight.For example, phrase " anhydrous basically Pharmaceutical composition " refers to that the water yield in this Pharmaceutical composition accounts for Pharmaceutical composition less than about 2% weight, preferably account for Pharmaceutical composition less than about 1% weight, more preferably account for Pharmaceutical composition less than about 0.5% weight, most preferably account for Pharmaceutical composition less than about 0.2% weight.
As using herein, term " growth hormone " refers to that biologically active and chemical constitution are substantially similar to the polypeptide of the growth hormone that produces in the animal brain hypophysis.This type of growth hormone comprises spontaneous growth hormone that the hypophysis cerebri somatotroph produces and by the transgenic microorganism growth hormone of escherichia coli (E.coli), other antibacterials or yeast expression for example.The growth hormone of this type of microorganisms can have the aminoacid sequence identical with the spontaneous growth hormone, perhaps can be to have the analog that one or more can provide the variant amino acid sequence of high bioactivity more or some other advantage.Growth hormone comprises and is used to improve the hormone that fat-thin ratio, feed efficient and various mammal include but not limited to the milk yield of domestic animal (for example milch cow), sheep, goat and pig.Representational growth hormone includes but not limited to cattle, sheep and the pig growth hormone of natural or microbial expression; The prolactin antagonist of cattle, pig or other animals; Somatotropin releasing factor; Human placental lactogen; And insulin like growth factor.
5.2 amino-acid ester
Amino-acid ester can be any aminoacid, promptly wherein amino acid whose carboxyl and C
1-C
22Amino acid whose any ester of alcohol esterification.Therefore, amino-acid ester has general formula (I):
Wherein:
R is an amino acid side chain; With
R
1Be C
1-C
22Alkyl.
To know easily that as those of ordinary skills it is possible that amino acid side chain R has various groups.For example, amino acid side chain can be to choose substituted alkyl wantonly.Suitable substituents includes but not limited to halogen, nitro, cyano group, sulfydryl, amino, hydroxyl, carboxyl, sulfo group, aryl and aromatics or non-aromatic heterocyclic group.The preferred amino acid side chain is C
1-C
10The straight or branched hydrocarbon, optional by sulfydryl, amino, hydroxyl, carboxyl, aryl or aromatics or the replacement of non-aromatic heterocyclic group; Aryl or aromatics or non-aromatic heterocyclic group.
Amino-acid ester can be the amino acid whose ester of naturally occurring aminoacid or synthetic preparation.Aminoacid can be D-aminoacid or L-aminoacid.Preferably, amino-acid ester is naturally occurring amino acid whose ester.More preferably, amino-acid ester is for being selected from following amino acid whose ester: glycine, alanine, valine, leucine, isoleucine, phenylalanine, agedoite, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine.
Alkyl R
1Can be any C
1-C
22Alkyl.Representational C
1-C
22Alkyl includes but not limited to methyl; Ethyl; Propyl group; Butyl; Amyl group; Hexyl; Heptyl; Octyl group; Nonyl; Decyl; Undecyl; Dodecyl; Tridecyl; Myristyl; Pentadecyl; Cetyl; Heptadecyl; Octadecyl; Pi-allyl; Cyclopenta; Cyclohexyl; Suitable-9-hexadecylene base; Suitable-9-vaccenic acid base; Suitable, suitable-9,12-18 carbon dialkylenes (octadecenyl) and suitable, suitable, suitable-9,12,15-18 carbon trialkenyl.
In one embodiment, R
1Be straight or branched, saturated or unsaturated alkyl.
In one embodiment, R
1Be straight chained alkyl.
In one embodiment, R
1Be branched alkyl.
In one embodiment, R
1Be saturated alkyl.
In one embodiment, R
1Be unsaturated alkyl.
In one embodiment, R
1Be straight chain, saturated alkyl.
In one embodiment, R
1Be straight chain, unsaturated alkyl.
In one embodiment, R
1Be C
6-C
18Alkyl.
In one embodiment, R
1Be C
8-C
18Alkyl.
In one embodiment, R
1Be C
10-C
18Alkyl.
In one embodiment, R
1Be C
6-C
18Straight chained alkyl.
In one embodiment, R
1Be C
6-C
18Branched alkyl.
In one embodiment, R
1Be C
6-C
18Saturated alkyl.
In one embodiment, R
1Be C
6-C
18Unsaturated alkyl.
In one embodiment, R
1Be C
8-C
18Straight chained alkyl.
In one embodiment, R
1Be C
8-C
18Branched alkyl.
In one embodiment, R
1Be C
8-C
18Saturated alkyl.
In one embodiment, R
1Be C
8-C
18Unsaturated alkyl.
In one embodiment, R
1Be C
10-C
18Straight chained alkyl.
In one embodiment, R
1Be C
10-C
18Branched alkyl.
In one embodiment, R
1Be C
10-C
18Saturated alkyl.
In one embodiment, R
1Be C
10-C
18Unsaturated alkyl.
Amino-acid ester can be by with those skilled in the art well-known method, J.March for example, Advanced Organic Chemistry, Reaction Mechanisms andStructure, the 4th edition, John Wiley ﹠amp; Sons, NY, 1992, the method for describing among the pp.393-400 is with aminoacid and formula R
1The pure esterification of-OH obtains.Aminoacid and formula R
1The alcohol of-OH can perhaps can prepare by the well-known method of those skilled in the art from commercial acquisition.With aminoacid and formula R
1During the pure esterification of-OH, may be necessary with some other functional group of blocking group protection aminoacid or alcohol, this blocking group can be removed after esterification.Those of ordinary skills will easily know with aminoacid and formula R
1Which kind of functional group needs protection before the pure esterification of-OH.Suitable blocking group is known to those skilled in the art, T.W.Greene etc. for example, Protective Groups in Organic Synthesis, those blocking groups of describing in the 3rd edition (1999).
5.3 amino acid amide
Amino acid amide can be any aminoacid, promptly wherein amino acid whose carboxyl and C
1-C
22The amine reaction produces amino acid whose any amide of amide.Therefore, amino acid amide has general formula (I):
Wherein:
R is an amino acid side chain;
R
3Be C
1-C
22Alkyl; And
R
4Be hydrogen or C
1-C
22Alkyl.
To know easily that as those of ordinary skills it is possible that amino acid side chain R has various groups.For example, aminoacid example chain can be to choose substituted alkyl wantonly.Suitable substituents includes but not limited to halogen, nitro, cyano group, sulfydryl, amino, hydroxyl, carboxyl, sulfo group, aryl and aromatics or non-aromatic heterocyclic group.The preferred amino acid side chain is C
1-C
10The straight or branched hydrocarbon, optional by sulfydryl, amino, hydroxyl, carboxyl, aryl or aromatics or the replacement of non-aromatic heterocyclic group; Aryl or aromatics or non-aromatic heterocyclic group.
Amino acid amide can be the amino acid whose amide of naturally occurring aminoacid or synthetic preparation.Aminoacid can be D-aminoacid or L-aminoacid.Preferably, amino-acid ester is naturally occurring amino acid whose ester.More preferably, amino-acid ester is for being selected from following amino acid whose ester: glycine, alanine, valine, leucine (leusine), isoleucine, phenylalanine, agedoite, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine.
R
3Group can be any C
1-C
22Alkyl.R
4Group can be hydrogen or any C
1-C
22Alkyl.Representational C
1-C
22Alkyl includes but not limited to methyl; Ethyl; Propyl group; Butyl; Amyl group; Hexyl; Heptyl; Octyl group; Nonyl; Decyl; Undecyl; Dodecyl; Tridecyl; Myristyl; Pentadecyl; Cetyl; Heptadecyl; Octadecyl; Pi-allyl; Cyclopenta; Cyclohexyl; Suitable-9-hexadecylene base; Suitable-9-vaccenic acid base; Suitable, suitable-9,12-18 carbon dialkylenes and suitable, suitable, suitable-9,12,15-18 carbon trialkenyl.
In one embodiment, R
4Be hydrogen, and R
3Be straight or branched, saturated or unsaturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be straight chained alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be branched alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be saturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be unsaturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be straight chain, saturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be straight chain, unsaturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
6-C
18Alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
6-C
18Straight chained alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
6-C
18Branched alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
6-C
18Saturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
6-C
18Unsaturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
8-C
18Alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
8-C
18Straight chained alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
8-C
18Branched alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
8-C
18Saturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
8-C
18Unsaturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
10-C
18Alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
10-C
18Straight chained alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
10-C
18Branched alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
10-C
18Saturated alkyl.
In one embodiment, R
4Be hydrogen, and R
3Be C
10-C
18Unsaturated alkyl.
In one embodiment, R
3And R
4Straight or branched, saturated or unsaturated alkyl, wherein R respectively do for oneself
3And R
4Can be identical or different.
In one embodiment, R
3And R
4C respectively does for oneself
6-C
18Alkyl, wherein R
3And R
4Can be identical or different.
In one embodiment, R
3And R
4C respectively does for oneself
8-C
18Alkyl, wherein R
3And R
4Can be identical or different.
In one embodiment, R
3And R
4C respectively does for oneself
10-C
18Alkyl, wherein R
3And R
4Can be identical or different.
In one embodiment, R
3And R
4The middle former sum that gives of carbon is at least 6.In one embodiment, R
3And R
4Middle the total number of carbon atoms is at least 8.In one embodiment, R
3And R
4Middle the total number of carbon atoms is at least 10.In one embodiment, R
3And R
4Middle the total number of carbon atoms is at least 12.
In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 6-30.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 8-30.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 10-30.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 12-30.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 6-22.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 8-22.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 10-22.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 12-22.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 6-18.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 8-18.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 10-18.In one embodiment, R
3And R
4The scope of middle the total number of carbon atoms is about 12-18.
Amino acid amide can be by with those skilled in the art well-known method, J.March for example, Advanced Organic Chemistry, Reaction Mechanisms andStructure, the 4th edition, John Wiley ﹠amp; Sons, NY, 1992, the method for describing among the pp.417-427 changes into amide groups with amino acid whose carboxyl and obtains.Usually, aminoacid is changed into amino acid derivativges for example amino-acid ester or amino acid whose acyl chlorides, this amino acid derivativges and formula NHR then
3R
4Amine reaction generate amino acid amide.Aminoacid and formula NHR
3R
4Amine can be from commercial acquisition, perhaps can be by the well-known method preparation of those skilled in the art.In the amino acid whose derivant of formation or with amino acid derivativges and formula NHR
3R
4Amine when reaction, may be necessary with some other functional group of blocking group protection amino acid derivativges or amine, this blocking group can be removed behind amidation process.Those of ordinary skills will easily know with amino acid whose derivant and formula NHR
3R
4Amine reaction before which kind of functional group need protection.Suitable blocking group is known to those skilled in the art, T.W.Greene etc. for example, Protective Groups in Organic Synthesis, those blocking groups of describing in the 3rd edition (1999).
5.4 carboxylic acid
Carboxylic acid can be any pharmaceutically acceptable carboxylic acid.Usually, carboxylic acid is C
1-C
22Carboxylic acid.Suitable carboxylic acid includes but not limited to acetic acid, propanoic acid, butanoic acid, valeric acid, capric acid, caproic acid, benzoic acid, caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, palmitic acid, oleic acid, linoleic acid plus linolenic acid.
In one embodiment, carboxylic acid is C
6-C
22Carboxylic acid.
In one embodiment, carboxylic acid is C
8-C
22Carboxylic acid.
In one embodiment, carboxylic acid is C
10-C
22Carboxylic acid.
In one embodiment, carboxylic acid is C
6-C
18Carboxylic acid.
In one embodiment, carboxylic acid is C
8-C
18Carboxylic acid.
In one embodiment, carboxylic acid is C
10-C
18Carboxylic acid.
In one embodiment, carboxylic acid is saturated or unsaturated fatty acid.
In one embodiment, carboxylic acid is a satisfied fatty acid.
In one embodiment, carboxylic acid is a unsaturated fatty acid.
In one embodiment, carboxylic acid is a dicarboxylic acids.Suitable dicarboxylic acids includes but not limited to oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid and 1,5-pentanedicarboxylic acid..
Carboxylic acid can perhaps can prepare by the well-known method of those skilled in the art from commercial acquisition.
In one embodiment, carboxylic acid is the N-acylamino acid.The N-acylamino acid has following general formula (II):
Wherein:
R is by amino acid side chain and as above-mentioned the definition; And
R
2Be formula-C (O)-R
5Acyl group, R wherein
5Be the C that replaces
1-C
21Alkyl, i.e. acyl group R
2Be C
1-C
22Acyl group.Representational formula-C (O)-R
5Acyl group includes but not limited to acetyl group, propiono, bytyry, caproyl, caproyl (caproyl), heptanoyl group, caprylyl, pelargonyl group, capryl, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecane acyl group, octadecanoyl, lauroyl, myristoyl, palmityl, stearyl, palmitoleoyl, oleoyl, inferior oleoyl, Caulis et Folium Lini acyl group and benzoyl.
In one embodiment, R
5Be C
5-C
21Alkyl, i.e. formula-C (O)-R
5Acyl group be C
6-C
22Acyl group.
In one embodiment, R
5Be C
7-C
21Alkyl, i.e. formula-C (O)-R
5Acyl group be C
8-C
22Acyl group.
In one embodiment, R
5Be C
9-C
21Alkyl, i.e. formula-C (O)-R
5Acyl group be C
10-C
22Acyl group.
In one embodiment, R
5Be C
5-C
17Alkyl, i.e. formula-C (O)-R
5Acyl group be C
6-C
18Acyl group.
In one embodiment, R
5Be C
7-C
17Alkyl, i.e. formula-C (O)-R
5Acyl group be C
8-C
18Acyl group.
In one embodiment, R
5Be C
9-C
17Alkyl, i.e. formula-C (O)-R
5Acyl group be C
10-C
18Acyl group.
In one embodiment, formula-C (O)-R
5Acyl group obtain by saturated or unsaturated fatty acid.
In one embodiment, formula-C (O)-R
5Acyl group be caproyl, lauroyl, myristoyl, palmityl, stearyl, palmitoleoyl, oleoyl, inferior oleoyl or Caulis et Folium Lini acyl group.
The aminoacid of N-acyl groupization can be by obtaining with the well-known method of those skilled in the art.For example, the aminoacid of N-acyl groupization can be used the well-known method of those skilled in the art, by with aminoacid and formula T-C (O)-R
5Carboxylic acid halides reaction obtain, wherein T is a halogen, preferred chlorine, R
1As above-mentioned definition.At aminoacid and formula T-C (O)-R
5Carboxylic acid halides when the N-acylation reaction takes place, may be necessary with some other functional group of blocking group protection aminoacid or carboxylic acid halides, this blocking group can be removed after acylation reaction.Those of ordinary skills will easily know with aminoacid and formula T-C (O)-R
5The carboxylic acid halides acidylate before which kind of functional group need protection.Suitable blocking group is known to those skilled in the art, T.W.Greene etc. for example, Protective Groups in Organic Synthesis, those blocking groups of describing in the 3rd edition (1999).
Carboxylic acid halides can be used the well-known method of those skilled in the art, J.March for example, Advanced Organic Chemistry, Reaction Mechanisms and Structure, the 4th edition, John Wiley; Sons, NY, 1992, the method for describing among the pp.437-8 obtains.For example, carboxylic acid halides can be by preparing carboxylic acid and thionyl chloride, thionyl bromide or thionyl Iod R.Acyl chlorides and acylbromide also can by with carboxylic acid respectively with Phosphorous chloride. or phosphorus tribromide prepared in reaction.Acyl chlorides also can pass through carboxylic acid and Ph
3P is prepared in reaction in carbon tetrachloride.Acyl fluorides can pass through carboxylic acid and cyanuric fluoride prepared in reaction.
5.5 pharmaceutically acceptable organic solvent
Any pharmaceutically acceptable organic solvent can be used in the Pharmaceutical composition of the present invention.Representational pharmaceutically acceptable organic solvent includes but not limited to ketopyrrolidine, N-N-methyl-2-2-pyrrolidone N-, Polyethylene Glycol, propylene glycol (promptly 1, ammediol), glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraethylene glycol (TEG), tetrahydrofurfuryl alcohol, glyceryl triacetate, Allyl carbonate, dimethyl acetylamide, dimethyl formamide, dimethyl sulfoxide and combination thereof.
In one embodiment, pharmaceutically acceptable organic solvent is a water-soluble solvent.Representational pharmaceutically acceptable water-miscible organic solvent is a glyceryl triacetate.
In one embodiment, pharmaceutically acceptable organic solvent is the solvent that dissolves each other with water.The representational pharmaceutically acceptable organic solvent that dissolves each other with water includes but not limited to glycerol formal, Polyethylene Glycol and propylene glycol.
In one embodiment, pharmaceutically acceptable organic solvent comprises ketopyrrolidine.In one embodiment, pharmaceutically acceptable organic solvent is the ketopyrrolidine of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises the N-N-methyl-2-2-pyrrolidone N-.In one embodiment, pharmaceutically acceptable organic solvent is the N-N-methyl-2-2-pyrrolidone N-of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises Polyethylene Glycol.In one embodiment, pharmaceutically acceptable organic solvent is the Polyethylene Glycol of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises propylene glycol.In one embodiment, pharmaceutically acceptable organic solvent is the propylene glycol of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises glycerol formal.In one embodiment, pharmaceutically acceptable organic solvent is the glycerol formal of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises isosorbide dimethyl ether.In one embodiment, pharmaceutically acceptable organic solvent is the isosorbide dimethyl ether of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises ethanol.In one embodiment, pharmaceutically acceptable organic solvent is the ethanol of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises dimethyl sulfoxide.In one embodiment, pharmaceutically acceptable organic solvent is the dimethyl sulfoxide of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises tetraethylene glycol (TEG).In one embodiment, pharmaceutically acceptable organic solvent is the tetraethylene glycol (TEG) of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises tetrahydrofurfuryl alcohol.In one embodiment, pharmaceutically acceptable organic solvent is the tetrahydrofurfuryl alcohol of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises glyceryl triacetate.In one embodiment, pharmaceutically acceptable organic solvent is the glyceryl triacetate of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises Allyl carbonate.In one embodiment, pharmaceutically acceptable organic solvent is the Allyl carbonate of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises dimethyl acetylamide.In one embodiment, pharmaceutically acceptable organic solvent is the dimethyl acetylamide of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent comprises dimethyl formamide.In one embodiment, pharmaceutically acceptable organic solvent is the dimethyl formamide of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent is the glycerol formal solution of the propylene glycol of essentially no another kind of organic solvent.
In one embodiment, pharmaceutically acceptable organic solvent is the glycerol formal solution of about 10% propylene glycol.
In one embodiment, pharmaceutically acceptable organic solvent is that FDA confirms as animals administer or consumes the solvent of using GRAS.
In one embodiment, pharmaceutically acceptable organic solvent is that FDA confirms to be the solvent that GRAS is used in people's administration or consumption.
In one embodiment, pharmaceutically acceptable organic solvent is gone up anhydrous substantially.Basically anhydrous pharmaceutically acceptable organic solvent is favourable, because they are unfavorable for the growth of antibacterial.Therefore, it is normally unnecessary to comprise antiseptic in anhydrous basically Pharmaceutical composition.
5.6 pharmaceutical active compounds
The example that is used for the pharmaceutically active agents of the present composition and method includes but not limited to the alpha-adrenergic agonist; the beta-adrenergic agonist; alpha-adrenergic blocking agent; beta-adrenergic blocking agent; aldose reductase inhibitor; anabolic agent (anabolics); analgesic (narcoticness and non-narcotic); androgen; anesthetis; appetite suppressant; anthelmintic (cestode for example; nematicide; Onchocerca; schistosomicide etc.); antiallergic agent; anti--ameboics; androgen antagonist; anti-pharyngalgia medicine; anti-arrhythmic; the arteriosclerosis medicine; anti-arthritic; antibiotic and other antimicrobial drugs; anticholinergic; anticonvulsant; antidepressants; antidiabetic drug; the diarrhea medicine; antidiuretic; estrogen antagonist; antifungal agent; Betimol; antigonadotropic; antigout drug; antihistaminic; antihyperlipoproteinemic; antihypertensive; antithyroid superfunction medicine; anti-loose medicine; antihypotensive; antithyroid hypofunction medicine; anti-inflammatory agent; antimalarial; antimicrobial; antimigraine; antinauseant; antineoplastic agent; antioxidant; antiparasitic; antiparkinsonian drug; anti-pheochromocytoma medicine; anti-lung sac worm medicine (anti-pneumocytis); antiproliferative agents; antiprotozoan agent (leishmaniasis for example; Trichomonas; trypanosomicide (trypansoma) etc.); pruritus; antipsoriatic (anti-psoratic agents); psychosis; antipyretic; rheumatism; the rickets medicine; seborrhea; antiseptic; spasmolytic; antithrombotic; cough medicine; antiulcerative; antilithic; venom; antiviral agents; antianxiety drugs; the benzodiazepine derivatives antagonist; bronchodilator; calcium channel blocker; calcium regulator; cardiac tonic; chelating agen; chemotherapeutant; the cholecystokinin antagonist; molten cholelithiasis medicine; choleretic; cholinergic agent; cholinesterase inhibitor; the acetylcholine esterase reactivator; central nervous system stimulant and medicament; Decongestant; diuretic; dopamine-receptor stimulant; the medicine of treatment or prevent irritation; external parasiticide; enzyme; enzyme inducer; estrogen; gastric secretion inhibitors; glucocorticoid; gonad stimulates principle; promoting sexual gland hormone; growth hormone; somatotropin releasing factor; growth stimulant; hemolytic agent; the heparin agonist; hepatoprotective; sleeping pill; immune system promoter; immunomodulator; immunosuppressant; lactogenic stimulates hormone; LH-RH stimulates agonist; lipotropic drug; the lupus erythematosus inhibitor; the mineral adrenocortical hormone; miotic; oxidase inhibitor; mucolytic agent; muscle relaxant; narcotic antagonist; neuroprotective; neotropics; ovarian hormone; odinagogue; pepsin inhibitor; the wriggling stimulant; progestogen; the prolactin antagonist inhibitor; prostaglandin (protoglandins); prostaglandin (prostoglandin) analog; protease inhibitor; respiratory stimulant; sclerosing agent; tranquilizer; steroid; the thrombolytic medicine; thyrotropin; percutaneous absorption fortifier; uricosuric agent; vasoconstrictor; vasodilation (brain for example; crown; peripheral vessels vasodilator etc.); blood vessel protective agent; vitamin; the vitamin source extract; vulnerary (includes but not limited to U.S. Patent number 5; 719; listed those in 197, its whole disclosed contents are attached to herein by reference) and combination.Other in addition or or the acceptable drug activating agent can for example find in the U.S. Patent number 6,221,383, its disclosed full content is attached to herein by reference.
In one embodiment, pharmaceutical active compounds is an antibacterial.Useful antibacterial example includes but not limited to beta-lactam antibiotic, for example penicillin, amoxicillin, ampicillin and cephalosporins; Macrolide antibiotics, for example amimycin and erythromycin; Tetracyclines, for example tetracycline, oxytetracycline and chlortetracycline; Neoproc; Quinolones, for example nalidixic acid and norfloxacin; Sulfonamides; Chloromycetin; Florfenicol; Thiamphenicol; Aminoglycoside, for example streptomycin, kanamycin and gentamycin; Nucleoside antibiotic class, for example Polyoxin AL; Actinorhodin; Bacitracin; Candicidin A; Ceftiofor; Clindamycin; Cycloheximide; Cycloserine; Fosfomycin; Griseofulvin; Metronidazole; Monensin; Novobiocin; Rifampicin, Streptothricin; Tetranactin (tetranactin); Tilmicosin; Tylosin; Actinomycin D; Amycin; Bleomycin A5 B2; Glycolipid class, for example moenomycin A; Ametycin; Nojirimycin (nojirimycin); Valinomycins and vancomycin (referring to, Bradford P.Smith for example, Large Animal Internal Medicine, the 2nd edition, Mosby, St.Louis, 1996, p.644, and S.Birchard and R.Sherding, Saunders Manual of Small Animal Practice, W.B.Saunders Company, Philadelphia, 1994, p.739).
In one embodiment, pharmaceutical active compounds is an antifungal.Useful antifungal example include but not limited to terbinafine, amphotericin B, ketoconazole (ketaconazole), miconazole, 5-flurocytosine, enilconazole, itraconazole, thiabendazole and iodide (referring to, Bradford P.Smith for example, Large Animal Internal Medicine, the 2nd edition, Mosby, St.Louis, 1996, p.576 with S.Birchard and R.Sherding, Saunders Manualof Small Animal Practice, W.B.Saunders Company, Philadelphia, 1994, p.576).
In one embodiment, pharmaceutical active compounds is an antiviral agents.Useful antiviral agents example include but not limited to interferon and adefovirdipivoxil (referring to, Bradford P.Smith for example, Large Animal Internal Medicine, the 2nd edition, Mosby, St.Louis, 1996, p.646).
In one embodiment, pharmaceutical active compounds is an antiparasitic.Useful antiparasitic example includes but not limited to benzimidazole, for example thiabendazole, fenbendazole, mebendazole, oxfendazole, oxibendazole, albendazole, parbendazole and febantel; Tetrahydropyridine class, for example morantel tartrate/Pyrantel Pamoate; Levamisole, organophosphorus compounds, for example haloxon, coroxon, metrifonate and dichlorvos; The piperazine salt; Ivermectin and phenothiazine (referring to, Bradford P.Smith for example, Large Animal InternalMedicine, the 2nd edition, Mosby, St.Louis, 1996, p.1688).
In one embodiment, pharmaceutical active compounds is an anti-inflammatory agent.Useful anti-inflammatory agent example includes but not limited to for example betamethasone of steroidal class; Cortical steroid is dexamethasone for example; Antihistaminic; And NSAID (non-steroidal anti-inflammatory drug), for example aspirin, flunixin meglumine, Phenylbutazone, diclofenac, naproxen, ketoprofen, carprofen and ibuprofen (referring to, Bradford P.Smith for example, Large Animal Internal Medicine, the 2nd edition, Mosby, St.Louis, 1996, p.645).
In one embodiment, pharmaceutical active compounds is a protein.
In one embodiment, pharmaceutical active compounds is a hormone.
In one embodiment, pharmaceutical active compounds is a peptide.
In one embodiment, pharmaceutical active compounds is an insulin.
In one embodiment, pharmaceutical active compounds is antidepressants.
In one embodiment, pharmaceutical active compounds is a fluoxetine.
Those of ordinary skills will readily appreciate which kind of pharmaceutical active compounds is that neutral pharmaceutical active compounds and which kind of pharmaceutical active compounds can form salt.
5.7 Pharmaceutical composition
8.7.1 comprise (i) amino-acid ester or amino acid amide, reach the (ii) Pharmaceutical composition of acidic drug reactive compound
Amino-acid ester can be above-mentioned any amino-acid ester.
Amino acid amide can be above-mentioned any amino acid amide.
The acidic drug reactive compound can be any acidic drug reactive compound.
In one embodiment, the acidic drug reactive compound is the anti-inflammatory agent that is selected from aspirin, flunixin, diclofenac, naproxen, ketoprofen, carprofen and ibuprofen.
In one embodiment, pharmaceutical active compounds is the nucleotide of phosphorylated, for example adefovirdipivoxil.
In one embodiment, Pharmaceutical composition is a solid.Be not wishing to be bound by theory, think that this solid is the salt that forms between amino-acid ester or amino acid amide and the acidic drug reactive compound, wherein this acidic drug reactive compound makes the alpha-amido of this amino-acid ester or amino acid amide protonated.
In one embodiment, Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.
Pharmaceutically acceptable organic solvent can be above-mentioned any pharmaceutically acceptable organic solvent.
In one embodiment, the Pharmaceutical composition that also comprises solvent is the suspension of solid particle in pharmaceutically acceptable organic solvent.Be not wishing to be bound by theory, think that solid particle comprises the salt that forms between amino-acid ester or amino acid amide and the acidic drug reactive compound, wherein this acidic drug reactive compound makes the alpha-amido of this amino-acid ester or amino acid amide protonated.
In one embodiment, the Pharmaceutical composition that comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
When the injection Pharmaceutical composition was injected in the entry, they formed precipitation.Be not wishing to be bound by theory, think that the alpha-amido of amino-acid ester or amino acid amide is protonated by the acidic drug reactive compound, be formed in the pharmaceutically acceptable organic solvent solvable but in water insoluble salt.Therefore, in the time of in Pharmaceutical composition is injected into animal body, the part of this Pharmaceutical composition precipitates in the injection site at least, so that drug depot to be provided.Be not wishing to be bound by theory, when thinking in Pharmaceutical composition is injected into animal body, pharmaceutically acceptable organic solvent spreads apart from the injection site, and aqueous body fluid spreads to the injection site, cause the increase of injection site water concentration, this causes the part precipitation and the formation drug depot of compositions at least.This precipitation can be solid, crystallization, viscosity block or gel form.Yet, be deposited in the injection site pharmaceutical active compounds storage that discharges pharmaceutical active compounds in time storehouse be provided.Also can form drug depot when the Pharmaceutical composition of suspension is in being injected into animal body.
The molar ratio of the acidic-group of acidic drug reactive compound and amino-acid ester or amino acid amide is generally about 1.5: 1, and preferred about 1.25: 1, more preferably from about 1.1: 1, most preferably from about 1: 1.Therefore, when the acidic drug reactive compound was the sub-carboxylic acid of simple substance, the molar ratio of acidic drug reactive compound and amino-acid ester or amino acid amide was about 1.5: 1, preferred about 1.25: 1, and more preferably from about 1.1: 1, most preferably from about 1: 1.Yet when the acidic drug reactive compound was dicarboxylic acids, the ratio of acidic drug reactive compound and amino-acid ester or amino acid amide was generally about 0.75: 1, preferred about 0.625: 1, and more preferably from about 0.55: 1, most preferably from about 0.5: 1.
When the molar ratio of the acidic-group of acidic drug reactive compound and amino-acid ester or amino acid amide greater than 1 the time, Pharmaceutical composition also will comprise the non-salt or the free form of acidic drug reactive compound.When giving animal, the compositions that also comprises the acidic drug reactive compound of free form provides predose or " prominent release (burst) " of this acidic drug reactive compound.Therefore, in certain embodiments, the molar ratio of the acidic-group of acidic drug reactive compound and amino-acid ester or amino acid amide is released to provide prominent greater than 1.
Yet for the acidic functionality in amount acidic drug reactive compound, Pharmaceutical composition comprises about 1 normal amino-acid ester or amino acid amide, so that essentially no free acidic drug reactive compound usually.For example, if the acidic drug reactive compound has an acidic functionality, for every normal acidic drug reactive compound, this acidity Pharmaceutical composition comprises about 1 normal amino-acid ester or amino acid amide.Yet if the acidic drug reactive compound has two acidic functionalities, for every normal acidic drug reactive compound, this acidity Pharmaceutical composition generally includes about 2 normal amino-acid ester or amino acid amides.
By changing the lipophile and/or the molecular weight of amino-acid ester or amino acid amide, the speed that change acidic drug reactive compound discharges from drug depot is possible.Generally speaking, amino-acid ester or amino acid amide lipophile are strong more, and drug release is slow more.The lipophile of amino-acid ester or amino acid amide and/or molecular weight can change by aminoacid and/or the alcohol (or amine) that change is used to form this amino-acid ester (or amino acid amide).For example, the lipophile of amino-acid ester and/or molecular weight can be by changing the R of this amino-acid ester
1Alkyl changes.Usually, increase R
1Length can increase the lipophile of amino-acid ester.Similarly, the lipophile of amino acid amide and/or molecular weight can be by changing the R of amino acid amide
3Or R
4Group changes.
The total amount of acidic drug reactive compound and amino-acid ester or amino acid amide accounts for the about 1-90% weight of Pharmaceutical composition usually, preferably account for the about 5-80% weight of Pharmaceutical composition, more preferably account for the about 7.5-70% weight of Pharmaceutical composition, most preferably account for the about 10-60% weight of Pharmaceutical composition.
In one embodiment, pharmaceutical active compounds is a flunixin.
In one embodiment, pharmaceutical active compounds is a flunixin, and amino-acid ester is the tryptophan monooctyl ester.
In one embodiment, pharmaceutical active compounds is a flunixin, and amino-acid ester is the tryptophan monooctyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol.
In one embodiment, pharmaceutical active compounds is a flunixin, amino-acid ester is the tryptophan monooctyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol, and the total amount of flunixin and tryptophan monooctyl ester accounts for the about 25-40% weight of compositions.
In one embodiment, pharmaceutical active compounds is a flunixin, amino-acid ester is the tryptophan monooctyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol, and the total amount of flunixin and tryptophan monooctyl ester accounts for the about 30-35% weight of compositions.
In one embodiment, pharmaceutical active compounds is a flunixin, and amino-acid ester is the tryptophan butyl ester.
In one embodiment, pharmaceutical active compounds is a flunixin, and amino-acid ester is the tryptophan butyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol.
In one embodiment, pharmaceutical active compounds is a flunixin, amino-acid ester is the tryptophan butyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol, and the total amount of flunixin and tryptophan butyl ester accounts for the about 20-35% weight of compositions.
In one embodiment, pharmaceutical active compounds is a flunixin, amino-acid ester is the tryptophan butyl ester, and pharmaceutically acceptable organic solvent is the glycerol formal solution of about 5% propylene glycol, and the total amount of flunixin and tryptophan butyl ester accounts for the about 25-32% weight of compositions.
In one embodiment, amino-acid ester or amide are lysine amino acid esters or amide.Be not wishing to be bound by theory, think lysine amino acid esters or amide by the description of following lysine ester, crosslinked with bimolecular acidic drug reactive compound:
R wherein
1Have above-mentioned implication, medicine-C (O) O-is the acidic drug reactive compound.
In one embodiment, the acidic drug reactive compound is the nucleotide of phosphorylated, for example adefovirdipivoxil.
The molar ratio of the amino of the acidic-group of pharmaceutical active compounds and lysine amino acid esters or amide is usually about 1.5: 1-1: in 1.5 the scope.In one embodiment, the molar ratio of the amino of the acidic-group of pharmaceutical active compounds and lysine amino acid esters or amide is about 1.25: 1-1: in 1.25 the scope.In one embodiment, the molar ratio of the amino of the acidic-group of pharmaceutical active compounds and lysine amino acid esters or amide is about 1.1: 1-1: in 1.1 the scope.In one embodiment, the molar ratio of the amino of the acidic-group of pharmaceutical active compounds and lysine amino acid esters or amide is about 1: 1.
In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 1: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 2: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 5: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 8: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 10: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds greater than about 12: 1.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds about 2: 1-5: in 1 the scope.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds about 2: 1-8: in 1 the scope.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds about 2: 1-10: in 1 the scope.In one embodiment, the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds about 2: 1-12: in 1 the scope.
In one embodiment, greater than about 1: 1, and some or all excessive amino of lysine amino acid esters or amide was neutralized by fatty acid the amino of lysine amino acid esters or amide with respect to the molar ratio of the acidic-group of pharmaceutical active compounds.During above-mentioned any fatty acid can be used for and the excessive amino of lysine amino acid esters or amide.
5.7.2 comprise (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, the (iii) Pharmaceutical composition of pharmaceutical active compounds or its pharmaceutically acceptable salt
Amino-acid ester can be above-mentioned any amino-acid ester.
Amino acid amide can be above-mentioned any amino acid amide.
Carboxylic acid can be above-mentioned any carboxylic acid.
In one embodiment, carboxylic acid is a fatty acid.
In one embodiment, carboxylic acid is the N-acylated amino.
In one embodiment, Pharmaceutical composition is a solid.Be not wishing to be bound by theory, think that this solid comprises the salt that forms between amino-acid ester or amino acid amide and the carboxylic acid, it is protonated that wherein this carboxylic acid makes the alpha-amido of this amino-acid ester or amino acid amide.
In one embodiment, Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.
Pharmaceutically acceptable organic solvent can be any above-mentioned pharmaceutically acceptable organic solvent.
In one embodiment, the Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is the suspension of solid particle in pharmaceutically acceptable organic solvent.Be not wishing to be bound by theory, think that solid particle is the salt that forms between amino-acid ester or amino acid amide and the carboxylic acid, it is protonated that wherein this carboxylic acid makes the alpha-amido of this amino-acid ester or amino acid amide.
In one embodiment, the Pharmaceutical composition that comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
Pharmaceutical active compounds can be neutral pharmaceutical active compounds, perhaps the pharmaceutically acceptable salt of alkalescence or acidic drug reactive compound.
In one embodiment, pharmaceutical active compounds is neutral pharmaceutical active compounds.When pharmaceutical active compounds is neutral pharmaceutical active compounds, in the carboxylic acid whenever the amount acidic-group, Pharmaceutical composition comprises about 1 normal amino-acid ester or amino acid amide.For example, if the carboxylic acid carboxylic acid that is simple substance, for every normal carboxylic acid, Pharmaceutical composition comprises about 1 normal amino-acid ester or amino acid amide, if and carboxylic acid is dicarboxylic acids, for every normal carboxylic acid, Pharmaceutical composition comprises about 2 normal amino-acid ester or amino acid amides.
In one embodiment, pharmaceutical active compounds is neutral pharmaceutical active compounds, and carboxylic acid is a fatty acid.
In one embodiment, pharmaceutical active compounds is neutral pharmaceutical active compounds, and carboxylic acid is the N-acylated amino.
The amount of neutral pharmaceutical active compounds in Pharmaceutical composition accounts for the about 1-90% weight of Pharmaceutical composition usually, preferably account for the about 5-80% weight of Pharmaceutical composition, more preferably account for the about 7.5-70% weight of Pharmaceutical composition, most preferably account for the about 10-60% weight of Pharmaceutical composition.
Yet, one of skill in the art will recognize that the amount of neutral pharmaceutical active compounds in the Pharmaceutical composition, can change in a wide range according to employed neutral pharmaceutical active compounds, solvent, amino-acid ester or amino acid amide and carboxylic acid in this Pharmaceutical composition.
The total amount of amino-acid ester in the Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent or amino acid amide and carboxylic acid, usually account for the about 2%-50% weight of Pharmaceutical composition, preferably account for the about 3%-35% weight of Pharmaceutical composition, more preferably account for the about 4%-25% weight of Pharmaceutical composition, even more preferably account for the about 5%-20% weight of Pharmaceutical composition, most preferably account for the about 5%-15% weight of Pharmaceutical composition.
In one embodiment, pharmaceutical active compounds is an insulin, carboxylic acid is a capric acid, amino-acid ester is a tyrosine ester in the last of the ten Heavenly stems, solvent is a glycerol formal, the molar ratio of capric acid and tyrosine ester in the last of the ten Heavenly stems is about 1: 1, and the amount of insulin accounts for the about 0.5-15% weight of Pharmaceutical composition, and the total amount of capric acid and tyrosine ester in the last of the ten Heavenly stems accounts for the about 15-25% weight of Pharmaceutical composition.
In one embodiment, pharmaceutical active compounds is a fluoxetine, carboxylic acid is a lauric acid, amino-acid ester is the tyrosine butyl ester, solvent is the glycerol formal solution of 10% propylene glycol, the amount of fluoxetine accounts for the about 5-30% weight of compositions, fluoxetine: lauric acid: the molar ratio of tryptophan butyl ester is about 1: 2: 1.Can give the Pharmaceutical composition of the present invention that dog contains fluoxetine and treat separation anxiety disorder (separation anxiety), and can give cat treatment spray foam (spraying).
In one embodiment, pharmaceutical active compounds is the pharmaceutically acceptable salt of acidity or alkalescent medicine reactive compound.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the acid.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the carboxylic acid.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the fatty acid.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the N-acylated amino.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and the alkali.
In one embodiment, the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and amino-acid ester or the amino acid amide.
In one embodiment, carboxylic acid is a fatty acid, and pharmaceutical active compounds is the pharmaceutically acceptable salt of acidity or alkalescent medicine reactive compound.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the acid.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the carboxylic acid.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the fatty acid.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the N-acylated amino.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and the alkali.
In one embodiment, carboxylic acid is a fatty acid, and the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and amino-acid ester or the amino acid amide.
In one embodiment, carboxylic acid is the N-acylated amino, and pharmaceutical active compounds is the pharmaceutically acceptable salt of acidity or alkalescent medicine reactive compound.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the acid.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the carboxylic acid.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the fatty acid.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the N-acylated amino.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and the alkali.
In one embodiment, carboxylic acid is the N-acylated amino, and the salt of pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and amino-acid ester or the amino acid amide.
When pharmaceutical active compounds is the salt of pharmaceutical active compounds, in the carboxylic acid whenever the amount acidic-group, Pharmaceutical composition comprises about 1 normal amino-acid ester or amino acid amide.
The total concentration of amino-acid ester or amino acid amide and carboxylic acid accounts for the about 2%-50% weight of Pharmaceutical composition usually in the Pharmaceutical composition, preferably account for the about 3%-35% weight of Pharmaceutical composition, more preferably account for the about 4%-25% weight of Pharmaceutical composition, even more preferably account for the about 5%-20% weight of Pharmaceutical composition, most preferably account for the about 5%-15% weight of Pharmaceutical composition.
The amount of the salt of acidity or alkalescent medicine reactive compound accounts for the about 1-90% weight of Pharmaceutical composition usually in the Pharmaceutical composition, preferably account for the about 5-80% weight of Pharmaceutical composition, more preferably account for the about 7.5-70% weight of Pharmaceutical composition, most preferably account for the about 10-60% weight of Pharmaceutical composition.
Yet, one of skill in the art will recognize that the amount of the salt of acidity in the Pharmaceutical composition or alkalescent medicine reactive compound, can change in a wide range according to employed pharmaceutical active compounds, solvent, amino-acid ester or amino acid amide and carboxylic acid in this Pharmaceutical composition.
Pharmaceutically acceptable organic solvent can be any above-mentioned pharmaceutically acceptable organic solvent.
Moreover, be not wishing to be bound by theory, think when the Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is injected into animal, this pharmaceutically acceptable organic solvent spreads apart from the injection site, and aqueous body fluid spreads to the injection site, cause the increase of injection site water concentration, this causes the part precipitation and the formation drug depot of said composition at least.Moreover when Pharmaceutical composition was injected into animal, the salt of amino-acid ester or amino acid amide and carboxylic acid precipitation formed the drug depot that slowly discharges this pharmaceutical active compounds.Yet the salt of pharmaceutical active compounds also can form precipitation.
In preferred embodiments, Pharmaceutical composition comprises the salt and the pharmaceutically acceptable organic solvent of amino-acid ester or amino acid amide, fatty acid, pharmaceutical active compounds, and wherein the salt of this pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and amino-acid ester or the amino acid amide.In this embodiment, when being injected into animal, Pharmaceutical composition forms when slowly discharging the drug depot of this pharmaceutical active compounds in time, the salt precipitation that forms between amino-acid ester or amino acid amide and the fatty acid, and the salt that forms between acidic drug reactive compound and amino-acid ester or amino acid amide precipitation.
In another preferred embodiment; Pharmaceutical composition comprises the salt and the pharmaceutically acceptable organic solvent of amino-acid ester or amino acid amide, N-acylated amino, pharmaceutical active compounds, and wherein the salt of this pharmaceutical active compounds is the salt that forms between acidic drug reactive compound and amino-acid ester or the amino acid amide.In this embodiment; when being injected into animal, Pharmaceutical composition forms when slowly discharging the drug depot of this pharmaceutical active compounds in time; the salt precipitation that forms between amino-acid ester or amino acid amide and the N-acylated amino, and the salt that forms between acidic drug reactive compound and amino-acid ester or amino acid amide precipitation.
When compositions comprises the salt of amino-acid ester or amino acid amide, carboxylic acid and pharmaceutical active compounds, the anion (and cation) of the salt that forms pharmaceutical active compounds can be recognized, anion (and cation) exchange of the salt between carboxylic acid and amino-acid ester or the amino acid amide will be and formed.For example; if the salt of pharmaceutical active compounds is the salt that forms between alkalescent medicine reactive compound and the fatty acid; and carboxylic acid is the N-acylated amino, and this Pharmaceutical composition will comprise following various material so: the salt between salt, amino-acid ester or amino acid amide between the salt between alkalescent medicine reactive compound and the fatty acid, alkalescent medicine reactive compound and the N-acylated amino and the salt between the fatty acid and amino-acid ester or amino acid amide and the N-acylated amino., this Pharmaceutical composition forms when slowly discharging the drug depot of pharmaceutical active compounds in time any in this class material or all can precipitate when being injected into animal.
By changing the lipophile and/or the molecular weight of amino-acid ester or amino acid amide, the speed that change acidic drug reactive compound discharges from drug depot is possible.Generally speaking, amino-acid ester or amino acid amide lipophile are strong more, and drug release is slow more.The lipophile of amino-acid ester or amino acid amide and/or molecular weight can change by aminoacid and/or the alcohol (or amine) that change is used to form this amino-acid ester (or amino acid amide).For example, the lipophile of amino-acid ester and/or molecular weight can be by changing the R of this amino-acid ester
1Alkyl changes.Usually increase R
1Length can increase the lipophile of this amino-acid ester.Similarly, the lipophile of amino acid amide and/or molecular weight can be by changing the R of this amino acid amide
3Or R
4Group changes.The speed that pharmaceutical active compounds discharges from drug depot also can change by lipophile and/or the molecular weight that changes carboxylic acid.Generally speaking, the lipophile of carboxylic acid is strong more, and drug release is slow more.The lipophile of carboxylic acid and/or molecular weight can change by the molecular weight that changes this carboxylic acid.Generally speaking, the molecular weight of carboxylic acid is big more, and drug release is slow more.Similarly, the lipophile of N-acylamino acid and/or molecular weight can be by changing the R of N-acylamino acid
5Group changes.
5.7.3 comprise (i) the N-acylamino acid and the (ii) Pharmaceutical composition of alkalescent medicine reactive compound
The N-acylamino acid can be any above-mentioned N-acylamino acid.
The alkalescent medicine reactive compound can be any alkalescent medicine reactive compound.
In one embodiment, the alkalescent medicine reactive compound is for being selected from the antibiotic of penicillin, streptomycin, azithromycin, Roxithromycin, tilmicosin, oxytetracycline and doxycycline (doxycyline).
In one embodiment, Pharmaceutical composition is a solid.Be not wishing to be bound by theory, think that this solid is the salt that forms between N-acylamino acid and the alkalescent medicine reactive compound, it is protonated that wherein this N-acylamino acid makes this alkalescent medicine reactive compound.
In one embodiment, Pharmaceutical composition also comprises pharmaceutically acceptable organic solvent.
Pharmaceutically acceptable organic solvent can be any above-mentioned pharmaceutically acceptable organic solvent.
In one embodiment, the Pharmaceutical composition that also comprises solvent is the suspension of solid particle in pharmaceutically acceptable organic solvent.Be not wishing to be bound by theory, think that solid particle is the salt that forms between N-acylamino acid and the alkalescent medicine reactive compound, it is protonated that wherein this N-acylamino acid makes this alkalescent medicine reactive compound.
In one embodiment, the Pharmaceutical composition that comprises pharmaceutically acceptable organic solvent is injectable, and forms precipitation when the injection entry.
In the time of in the injection Pharmaceutical composition injection that also comprises solvent is intake, their form precipitation usually.Be not wishing to be bound by theory, think that the carboxyl of N-acylamino acid makes the alkalescent medicine reactive compound protonated, form and dissolve in pharmaceutically acceptable organic solvent but water-fast salt.Therefore, when Pharmaceutical composition was injected into animal, the part of this Pharmaceutical composition precipitated so that drug depot to be provided in the injection site at least.Be not wishing to be bound by theory, think when Pharmaceutical composition is injected into animal, pharmaceutically acceptable organic solvent spreads apart from the injection site, and aqueous body fluid spreads to the injection site, cause the increase of injection site water concentration, this causes the part precipitation and the formation drug depot of said composition at least.This precipitation can be solid, crystallization, viscosity block or gel form.Yet this is deposited in the storage storehouse that the injection site provides pharmaceutical active compounds, and this storage storehouse can discharge this pharmaceutical active compounds in time.For the Pharmaceutical composition of suspension also can form drug depot when being injected into animal.
The molar ratio of the basic group of alkalescent medicine reactive compound and N-acylamino acid is generally about 1.5: 1, and preferred about 1.25: 1, more preferably from about 1.1: 1, most preferably from about 1: 1.Therefore, when the alkalescent medicine reactive compound was an alkali valency chemical compound, the molar ratio of alkalescent medicine reactive compound and N-acylamino acid was about 1.5: 1, preferred about 1.25: 1, and more preferably from about 1.1: 1, most preferably from about 1: 1.Yet when the alkalescent medicine reactive compound was the bibasic chemical compound, the ratio of alkalescent medicine reactive compound and N-acylamino acid was generally about 0.75: 1, preferred about 0.625: 1, and more preferably from about 0.55: 1, most preferably from about 0.5: 1.
When the molar ratio of the basic group of alkalescent medicine reactive compound and N-acylamino acid greater than 1 the time, Pharmaceutical composition also will comprise the non-salt or the free form of this alkalescent medicine reactive compound.The compositions that also comprises the alkalescent medicine reactive compound of free form provides predose or " prominent the releasing " of this alkalescent medicine reactive compound.Therefore, in certain embodiments, the molar ratio of the basic group of alkalescent medicine reactive compound and N-acylamino acid is released to provide prominent greater than 1.
Yet, usually in the alkalescent medicine reactive compound whenever the amount basic functionality, Pharmaceutical composition comprises about 1 normal N-acylamino acid, so that essentially no free alkalescent medicine reactive compound.For example, if the alkalescent medicine reactive compound has a basic functionality, for every normal alkalescent medicine reactive compound, the basic medicinally compositions comprises about 1 normal N-acylamino acid.Yet if the alkalescent medicine reactive compound has two basic functionalities, for every normal alkalescent medicine reactive compound, Pharmaceutical composition generally includes about 2 normal N-acylamino acids.
By changing the lipophile and/or the molecular weight of N-acylamino acid, the speed that change alkalescent medicine reactive compound discharges from drug depot is possible.Generally speaking, N-acylamino acid lipophile is strong more, and drug release is slow more.The lipophile of N-acylamino acid and/or molecular weight can change by aminoacid and/or the acyl group that change is used to form this N-acylamino acid.For example, the lipophile of N-acylamino acid and/or molecular weight can be by changing the R of N-acylamino acid
5Alkyl changes.Usually, increase R
5Length can increase the lipophile of N-acylamino acid.
The total amount of Pharmaceutical composition neutral and alkali pharmaceutical active compounds and N-acylamino acid accounts for the about 1-90% weight of Pharmaceutical composition usually; preferably account for the about 5-80% weight of Pharmaceutical composition; more preferably account for the about 7.5-70% weight of Pharmaceutical composition, most preferably account for the about 10-60% weight of Pharmaceutical composition.
In one embodiment, the alkalescent medicine reactive compound is a fluoroquinolone.This fluoroquinolone can be any fluoroquinolone well known by persons skilled in the art.The representational fluoroquinolones that can be used in the present composition and the method includes but not limited to BE 870,576, U.S.Pat.No.4,448,962, DE 3,142, and 854, EP 047,005, EP 206,283, BE 887,574, EP 221,463, EP 140,116, EP 131,839, EP 154,780, EP 078,362, EP310,849, EP 520,240, U.S.Pat.No.4,499,091, U.S.Pat.No.4,704,459, U.S.Pat.No.4,795,751, U.S.Pat.No.4,668,784 and U.S.Pat.No.5,532, those that describe in 239, its content is attached to herein by reference.
The representational fluoroquinolones that can be used in the present composition and the method includes but not limited to that ciprofloxacin is (with Cipro
Commercially available), enrofloxacin is (with Baytril
Commercially available), enoxacin is (with Penetrex
Commercially available), Gatifloxacin is (with Tequin
Commercially available), Gemifloxacin is (with Factive
Commercially available), levofloxacin is (with Levaquin
Commercially available), lomefloxacin is (with Maxaquin
Commercially available), Moxifloxacin is (with Avelox
Commercially available), norfloxacin is (with Noroxin
Commercially available), ofloxacin is (with Floxin
Commercially available), Sparfloxacin is (with Zagam
Commercially available), trovafloxacin is (with Trovan
Commercially available), difloxacin, cinofloxacin, pefloxacin, tosufloxacin, temafloxacin, fleroxacin (flerofloxacin), amifloxacin, the husky star (benofloxacin) of times promise, danofloxacin, fleroxacin, Marbofloxacin, ruflocaxin and Sarafloxacin.
In one embodiment, fluoroquinolone is a ciprofloxacin.
In one embodiment, fluoroquinolone is an enrofloxacin.
In one embodiment, fluoroquinolone is a Gatifloxacin.
In one embodiment, fluoroquinolone is a Gemifloxacin.
In one embodiment, fluoroquinolone is a levofloxacin.
In one embodiment, fluoroquinolone is a lomefloxacin.
In one embodiment, fluoroquinolone is a Moxifloxacin.
In one embodiment, fluoroquinolone is an ofloxacin.
In one embodiment, fluoroquinolone is a Sparfloxacin.
In one embodiment, fluoroquinolone is a trovafloxacin.
In one embodiment, fluoroquinolone is a difloxacin.
In one embodiment, fluoroquinolone is cinofloxacin.
In one embodiment, fluoroquinolone is a pefloxacin.
In one embodiment, fluoroquinolone is a tosufloxacin.
In one embodiment, fluoroquinolone is a temafloxacin.
In one embodiment, fluoroquinolone is a fleroxacin.
In one embodiment, fluoroquinolone is an amifloxacin.
In one embodiment, fluoroquinolone is the husky star of times promise.
In one embodiment, fluoroquinolone is a danofloxacin.
In one embodiment, fluoroquinolone is a fleroxacin.
In one embodiment, fluoroquinolone is a Marbofloxacin.
In one embodiment, fluoroquinolone is ruflocaxin.
In one embodiment, fluoroquinolone is a Sarafloxacin.
5.7.4 the general features of Pharmaceutical composition
Usually, when in the compositions of the present invention injection entry, what produced is precipitated as viscosity block or gel.Usually, the viscosity of viscosity block or gel is about 10, and 000cP-150 is in the scope of 000cP.In one embodiment, the viscosity of viscosity block or gel is about 50, and 000cP-150 is in the scope of 000cP.In one embodiment, the viscosity of viscosity block or gel is at about 65,000 centipoises (cP)-150, in the scope of 000cP.In one embodiment, the viscosity of viscosity block or gel is at about 75,000 centipoises (cP)-150, in the scope of 000cP.The viscosity of viscosity block or gel can be measured by the following method: Pharmaceutical composition is injected in the entry, viscosity block or gel are provided, remove by filter water and pharmaceutically acceptable organic solvent with 0.22 μ m filter, collect this viscosity block or gel, measure the viscosity of this viscosity block or gel then.For example can use Brookfield DV-E viscometer (commercial can be, MA obtain) to measure viscosity from Brookfield of Middleboro.In another embodiment, be precipitated as solid, promptly anti-mobile.In another embodiment, solid is a crystalline solid.
By change the lipophile and/or the molecular weight of amino-acid ester or amino acid amide, the speed that the may command pharmaceutical active compounds discharges from drug depot.Usually, if the lipophile of amino-acid ester is strong more, drug release is slow more.The lipophile of amino-acid ester and/or molecular weight can be by changing the R of this amino-acid ester
1Alkyl changes.Usually, increase R
1Length can increase the lipophile of amino-acid ester.Similarly, the lipophile of amino acid amide and/or molecular weight can be by changing the R of this amino acid amide
3Or R
4Group changes.
The carboxylic acid that is used for Pharmaceutical composition also influences the rate of release of pharmaceutical active compounds from drug depot.Similarly, when carboxylic acid was the N-acylamino acid, the rate of release of pharmaceutical active compounds from drug depot can be controlled by the lipophile and/or the molecular weight that change this N-acylamino acid.Moreover if the lipophile of carboxylic acid or N-acylamino acid is strong more, drug release is slow more.The lipophile of carboxylic acid and/or molecular weight can change by the number that changes carbon atom in the carboxylic acid.The lipophile of N-acylamino acid and/or molecular weight can be by changing acyl group R
2R
5Alkyl is promptly by change formula-C (O)-R
5Acyl group change.
Pharmaceutical composition can also comprise well-known other excipient of one or more those of ordinary skills or additive.For example, pharmaceutical preparation can comprise the antiseptic that suppresses growth of microorganism.Suitable antiseptic includes but not limited to parabens, for example methyl hydroxybenzoate, ethyl ester and propyl ester; Methaform; Sodium benzoate; Chlorination myristyl-γ-picoline ; Benzylalcohol and ethanol.When existing, antiseptic exists with the amount of about 5mg-250mg/mL Pharmaceutical composition usually, and preferably exists with the amount of about 5mg-100mg/mL Pharmaceutical composition.
In one embodiment, compositions comprises for example lignocaine of local anesthetic, to alleviate the pain of injection site.
Solid pharmaceutical composition can also comprise the well-known other excipient of those of ordinary skills, for example binding agent, diluent, lubricant.Described suitable excipient example among the Remington ' s PharmaceuticalSciences (Alfonso Gennaro writes, the 19th edition, 1995), it is attached to herein by reference.Therefore, solid pharmaceutical composition can be used the well-known method of those skilled in the art, is mixed with the tablet (Remington ' sPharmaceutical Sciences (Alfonso Gennaro writes, the 19th edition, 1995) of oral administration.
Similarly, the Pharmaceutical composition of gel form can be mixed with the medicament of oral administration by Pharmaceutical composition being enclosed for example hard or Perle of capsule.
The component of Pharmaceutical composition (amino-acid ester or amino acid amide, carboxylic acid, organic solvent, pharmaceutical active compounds and any other optional components) preferably can be biocompatible and nontoxic, can be absorbed in time simply and/or metabolism by health.
5.8 preparation Pharmaceutical composition
Comprise (i) amino-acid ester or amino acid amide in order to prepare, (ii) acidic drug reactive compound, reach the (iii) Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, amino-acid ester or amino acid amide and acidic drug reactive compound can be dissolved in the pharmaceutically acceptable organic solvent simply, solution (desired about 90% quantity of solvent in the usually final Pharmaceutical composition) is provided; Other excipient and/or additive can be dissolved in this solution then; And then add pharmaceutically acceptable organic solvent, so that the concentration of amino-acid ester or amino acid amide and acidic drug reactive compound desired in this Pharmaceutical composition to be provided; Then, amino-acid ester or amino acid amide and acidic drug reactive compound and other excipient and/or the solution of additive can be filtered, preferred aseptic filtration, Direct Filtration is in bottle.
Comprise (i) amino-acid ester or amino acid amide and the (ii) solid pharmaceutical composition of acidic drug reactive compound, with be used for preparation and comprise (i) amino-acid ester or amino acid amide, (ii) acidic drug reactive compound and the (iii) identical method preparation of Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, and pharmaceutically acceptable organic solvent can be removed by evaporation simply.In one embodiment, pharmaceutically acceptable organic solvent decompression is removed.Perhaps, comprise (i) amino-acid ester or amino acid amide, (ii) acidic drug reactive compound and (iii) the Pharmaceutical composition dilutable water of pharmaceutically acceptable organic solvent are to provide solid precipitation, and this solid precipitation is collected by filtering, and optionally drying.The gained solid pharmaceutical composition can be chosen pulverizing wantonly, so that littler granule to be provided.Excipient also can join in the gained solid pharmaceutical composition.
Similarly, comprise (i) amino-acid ester or amino acid amide in order to prepare, (ii) carboxylic acid, the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, reach the (iv) Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, can be simply the pharmaceutically acceptable salt of amino-acid ester or amino acid amide, carboxylic acid and neutral pharmaceutical active compounds or pharmaceutical active compounds be dissolved in the pharmaceutically acceptable organic solvent, solution (desired about 90% quantity of solvent in the usually final Pharmaceutical composition) is provided; Then, other excipient and/or additive can be dissolved in this solution; Then, add pharmaceutically acceptable organic solvent again, with the concentration of pharmaceutically acceptable salt that amino-acid ester desired in this Pharmaceutical composition or amino acid amide, carboxylic acid and neutral pharmaceutical active compounds or pharmaceutical active compounds are provided; Then, the pharmaceutically acceptable salt of amino-acid ester or amino acid amide, carboxylic acid, neutral pharmaceutical active compounds or pharmaceutical active compounds and other excipient and/or the solution of additive can be filtered, preferred aseptic filtration, Direct Filtration is in bottle.
Comprise (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, and the solid pharmaceutical composition of the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, with be used for preparation and comprise (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, and the (iv) identical method preparation of Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, and pharmaceutically acceptable organic solvent can be removed by evaporation simply.In one embodiment, pharmaceutically acceptable organic solvent decompression is removed.Perhaps, comprise (i) amino-acid ester or amino acid amide, (ii) carboxylic acid, the pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds, and the Pharmaceutical composition dilutable water of pharmaceutically acceptable organic solvent, so that solid precipitation to be provided, and this solid precipitation collects by filtering, and optionally drying.The gained solid pharmaceutical composition can be chosen pulverizing wantonly, so that littler granule to be provided.Excipient also can join in the gained solid pharmaceutical composition.
Similarly, comprise (i) N-acylamino acid in order to prepare, (ii) alkalescent medicine reactive compound, reach the (iii) Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, can simply N-acylamino acid and alkalescent medicine reactive compound be dissolved in the pharmaceutically acceptable organic solvent, solution (desired about 90% quantity of solvent in the usually final Pharmaceutical composition) is provided; Then, other excipient and/or additive can be dissolved in this solution; Then, add pharmaceutically acceptable organic solvent again, so that the concentration of N-acylamino acid and alkalescent medicine reactive compound desired in this Pharmaceutical composition to be provided; Then, N-acyl amino acid ester and alkalescent medicine reactive compound and other excipient and/or the solution of additive can be filtered, preferred aseptic filtration, Direct Filtration is in bottle.
Comprise (i) the N-acylamino acid and the (ii) solid pharmaceutical composition of alkalescent medicine reactive compound; with be used for preparation and comprise (i) N-acylamino acid; (ii) alkalescent medicine reactive compound; and the (iii) identical method preparation of Pharmaceutical composition of the present invention of pharmaceutically acceptable organic solvent, and pharmaceutically acceptable organic solvent can be removed by evaporation simply.In one embodiment, pharmaceutically acceptable organic solvent decompression is removed.Perhaps, comprise (i) N-acylamino acid, (ii) alkalescent medicine reactive compound, and the (iii) Pharmaceutical composition dilutable water of pharmaceutically acceptable organic solvent, so that solid precipitation to be provided, and this solid precipitation collects by filtering, and optionally drying.The gained solid pharmaceutical composition can be chosen pulverizing wantonly, so that littler granule to be provided.Excipient also can join in the gained solid pharmaceutical composition.
Pharmaceutical composition can be sterilized with autoclave.
The invention still further relates to the method for preparing Pharmaceutical composition of the present invention.
5.9 the method for treatment animal disease
The invention still further relates to the method for treatment animal disease.This method comprises the pharmaceutical active compounds of the animal effective dose that needs are arranged.Pharmaceutical composition of the present invention can be through injection or oral administration.
Solid pharmaceutical composition can be by being implanted to the animal subcutaneous administration with this solid pharmaceutical composition.Yet solid pharmaceutical composition also can be by injecting the suspension administration of solid pharmaceutical composition in pharmaceutically acceptable organic solvent to animal.
But the Pharmaceutical composition of the present invention of solid, crystallization, viscosity block or gel form is oral administration also.For example, capsule is enclosed in the pharmaceutical preparation of solid, crystallization, viscosity block or gel form, providing can peroral administration dosage form.In addition, solid pharmaceutical composition of the present invention can with excipient for example binding agent, diluent or mix lubricant, and be mixed with tablet so that peroral administration dosage form to be provided.Referring to, Remington ' s PharmaceuticalSciences for example, Alfonso Gennaro writes, and the 19th edition, 1995), it is attached to herein by reference.Peroral dosage form can be designed under one's belt immediately or almost discharge immediately the form of pharmaceutical active compounds, or is designed to provide under one's belt the form that continues to discharge pharmaceutical active compounds.The rate of release of pharmaceutical active compounds changes by lipophile and/or the molecular weight that changes each component in the Pharmaceutical composition.
The injection Pharmaceutical composition is by coming to animals administer to animal injection Pharmaceutical composition.When the injection Pharmaceutical composition was injected into animal, Pharmaceutical composition forms provided pharmaceutical active compounds to continue the storage storehouse that discharges.Be the Pharmaceutical composition of the suspension of solid pharmaceutical composition in pharmaceutically acceptable organic solvent, also can form when being injected into animal provides pharmaceutical active compounds to continue the storage storehouse that discharges.The component of Pharmaceutical composition, promptly amino-acid ester or amino acid amide, carboxylic acid and pharmaceutically acceptable organic solvent are biocompatible and are nontoxic, and are absorbed in time simply and/or metabolism by health.Pharmaceutical composition of the present invention also can pass through other administrations, and these approach include but not limited to part, per os, rectum, vagina and nose approach.
The pharmaceutical active compounds that Pharmaceutical composition of the present invention can offer animal effective dose continues to reach 15 days even the longer time, this depends on the component of Pharmaceutical composition, i.e. pharmaceutical active compounds or its pharmaceutically acceptable salt, amino-acid ester, carboxylic acid and pharmaceutically acceptable organic solvent.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 3 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 4 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 6 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 8 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 10 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 12 days effective doses most.
In one embodiment, Pharmaceutical composition provides pharmaceutical active compounds or its pharmaceutically acceptable salt that reaches about 15 days effective doses most.
Pharmaceutical composition can be used for human medicine and veterinary's medicine.Pharmaceutical composition is particularly useful for veterinary's medicine.
In one embodiment, animal is behaved.
In one embodiment, animal is a cat.
In one embodiment, animal is a Canis familiaris L..
In one embodiment, animal is a cattle.
In one embodiment, animal is a pig.
In one embodiment, animal is a sheep.
In one embodiment, animal is a horse.
Usually, the Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent is with about 0.2mL-15mL, preferably about 0.5mL-12mL, the more preferably from about amount of 1mL-10mL injection.Exact dose to be given will depend on the order of severity of disease and by the animal treated, and can be according to the judgement decision of the situation of practitioner and/or each animal.Littler animal is accepted littler volume injected usually.For example, the volume injected of cat is generally about 1mL, and the volume injected of Canis familiaris L. is usually between about 1mL-2mL.Yet to large animal for example cattle and Ma Eryan, volume injected can arrive 10mL greatly, and even bigger.The amount that gives the Pharmaceutical composition of animal can determine by standard clinical techniques, in addition, can choose wantonly adopt external or in vivo test to help to determine best dosage range.
The Pharmaceutical composition that also comprises pharmaceutically acceptable organic solvent for example can be by intramuscular injection, peritoneal injection or subcutaneous injection administration.
Solid pharmaceutical composition is usually by using the well-known method of those of ordinary skills, to contain the 0.01-2g that has an appointment, the solid pharmaceutical composition of preferably about 0.2g-1.5g pharmaceutical active compounds or its pharmaceutically acceptable salt is implanted to the animal skins administration of getting off.Solid pharmaceutical composition also can come administration by the suspension of injection solid composite in solvent.Solid pharmaceutical composition can be suspended in aqueous solvent or the organic solvent.
Peroral administration Pharmaceutical composition is generally capsule or tablet form, and contains the 0.001g-2g that has an appointment usually, preferably about 0.01g-1.5g pharmaceutical active compounds or its pharmaceutically acceptable salt.
Pharmaceutical composition of the present invention also can pass through other administrations, and these approach include but not limited to part, rectum, vagina and nose approach.
By the lasting release of pharmaceutical active compounds is provided, the reduction that Pharmaceutical composition is favourable toxicity, particularly to toy for example cat and Canis familiaris L..Therefore, Pharmaceutical composition of the present invention has than the immediate release formulations of routine and better treats curve.Relate to by inject Pharmaceutical composition of the present invention to animal and pharmaceutical active compounds is given the inventive method of animal, permission gives animal with pharmaceutical active compounds, if these chemical compounds are with the dosage form administration that exists at present then may toxigenicity, even cause being treated animal dead.By the lasting release of pharmaceutical active compounds is provided, Pharmaceutical composition of the present invention does not need administration continually, and is therefore easier, more convenient and more cost is effective to administration person than the conventional method that gives pharmaceutical active compounds yet.
5.10 kit
The present invention includes the kit of the pharmaceutical active compounds administration that can simplify animal.The typical kit of the present invention comprises the unit dosage form of Pharmaceutical composition of the present invention, and in one embodiment, unit dosage form is the container that contains Pharmaceutical composition of the present invention, bottle for example, and this container can be sterilized.Kit can also comprise label, or instructs and use pharmaceutical active compounds with sanatory printing description.In another embodiment, kit comprises the unit dosage form of Pharmaceutical composition of the present invention and is used for the syringe of Pharmaceutical composition administration.
Proposing following examples and be used for helping to understand the present invention, is of the present invention concrete restriction to described herein and claimed and should not be interpreted into.Of the present invention this type of changes, and it is alternative to be included in being equal to of the known now or latest developments of in those skilled in the art's understandability scope all, and minor alteration is all thought in this article the scope of the invention in the variation of preparation or the EXPERIMENTAL DESIGN.
6. embodiment
6.1 the preparation of amino-acid ester
Tryptophan butyl ester: 1g tryptophan butyl ester hydrochlorate (by Sigma-Aldrich, St.Louis, MO (www.sima-aldrich.com) sells) is suspended in the 25mL dichloromethane, and 600 μ L triethylamines are joined in this suspension under stirring.Continue to stir 15 minutes, and gained solution is transferred in the separatory funnel.Organic solution is with 25mL water washing twice, then with the washing of 25mL saturated sodium bicarbonate aqueous solution.Organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure then obtains the tryptophan butyl ester.With mass spectrum confirmation its structure.
Tryptophan monooctyl ester: 4g tryptophan butyl ester hydrochlorate (by Sigma-Aldrich, St.Louis, MO (www.sima-aldrich.com) sells) is suspended in the 100mL dichloromethane, and the 3mL triethylamine is joined in this suspension under stirring.Continue to stir 15 minutes, and gained solution is transferred in the separatory funnel.Organic solution is with 25mL water washing twice, then with the washing of 25mL saturated sodium bicarbonate aqueous solution.Organic layer anhydrous sodium sulfate drying, and concentrating under reduced pressure then obtains the tryptophan monooctyl ester.With mass spectrum confirmation its structure.
The tyrosine butyl ester: 18.19g tyrosine is suspended in the solution of the 9.8g concentrated sulphuric acid, 40mL water, 40mL butanols and the 200mL toluene that place the 500mL round-bottomed flask, and this round-bottomed flask is equipped with condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Gained solution is cooled off in ice bath, and it is biphase that solution is divided into.Discard the upper strata, and keep lower floor-oily slurry.This slurry is mixed with enough 5% sodium bicarbonate aqueous solution, with in and acid impurities, obtain solid, filter and collect this solid, and use cold water washing.Gained solid recrystallization in ethyl acetate.
The isoleucine butyl ester: the 26.23g isoleucine is dissolved in the solution of the 20g concentrated sulphuric acid, 20mL water, 40mL butanols and the 200mL toluene that place the 500mL round-bottomed flask, and this round-bottomed flask is equipped with condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, and with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, and, obtain isoleucine butyl ester colourless liquid with the distillation of gained liquid vacuum.
The phenylalanine butyl ester: the 16.52g isoleucine is dissolved in the solution of the 10g concentrated sulphuric acid, 20mL water, 20mL butanols and the 200mL toluene that place the 500mL round-bottomed flask, and this flask equipped has condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, and with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, and, obtain the phenylalanine butyl ester with the distillation of gained liquid vacuum.
The phenylalanine monooctyl ester: the 16.52g phenylalanine is dissolved in the solution of the 10g concentrated sulphuric acid, 20mL water, 20mL capryl alcohol and the 120mL toluene that place the 500mL round-bottomed flask, and this round-bottomed flask is equipped with condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, and with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains white solid phenylalanine monooctyl ester then, and this solid silicagel column purification is with 1: 9 methanol: the dichloromethane mixture eluting.
The phenylalanine dodecyl ester: the 16.52g phenylalanine is dissolved in the solution of the 10g concentrated sulphuric acid, 20mL water, 20mL dodecanol and the 120mL toluene that place the 500mL round-bottomed flask, and this flask equipped has condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, and with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains solid styrene-acrylic propylhomoserin dodecyl ester then, and this solid silicagel column purification, eluent are 1: 9 methanol: dichloromethane mixture.
The tyrosine monooctyl ester: 9.06g tyrosine is dissolved in the solution of the 10g concentrated sulphuric acid, 20mL water, 10mL capryl alcohol and the 200mL toluene that place the 500mL round-bottomed flask, and this flask equipped has condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, and with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, obtain milk.In this milk, add about 150mL ethyl acetate, obtain biphase.Aqueous phase discarded, organic facies is washed with saturated brine, and uses anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains white solid tyrosine monooctyl ester, and this solid silicagel column purification, eluent are 1: 9 methanol: dichloromethane mixture.
The isoleucine monooctyl ester: the 13.1g isoleucine is dissolved in the solution of the 10g concentrated sulphuric acid, 20mL water, 20mL capryl alcohol and the 200mL toluene that place the 500mL round-bottomed flask, and this flask places oil bath, is equipped with condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, with the dilution of 120mL ethyl acetate, organic layer washs with saturated sodium bicarbonate aqueous solution, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, and, obtain colourless liquid isoleucine monooctyl ester with the distillation of gained liquid.
The proline butyl ester: the 34.5g proline is suspended in the solution of the 35g concentrated sulphuric acid, 40mL water, 120mL butanols and the 200mL toluene that place the 500mL round-bottomed flask, and this flask equipped has condenser and Dean-Stark device.Gained solution is heated in reflux temperature, till no longer including water and distilling out.Then gained solution is cooled to room temperature, with saturated sodium bicarbonate aqueous solution washing, with in and acid impurities, with the saturated brine washing, and use anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, and, obtain colourless liquid proline butyl ester with the distillation of gained liquid.
6.2 contain the Pharmaceutical composition of flunixin and amino-acid ester
The compositions that contains flunixin and tryptophan monooctyl ester salt: weighing 1.5g flunixin and 1.766g tryptophan monooctyl ester place the 10mL volumetric flask.Add the 0.5mL propylene glycol in this volumetric flask, this volumetric flask adds to about 90% volume with glycerol formal.Then this volumetric flask is placed on the electromagnetic shaker, and about 30 minutes of ultrasonic once in a while jolting, clear solutions obtained.Then this volumetric flask is added to the 10mL volume with glycerol formal.When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
The compositions that contains flunixin and tryptophan butyl ester salt: weighing 0.75g flunixin and 0.73g tryptophan butyl ester place the 5mL volumetric flask.Add the 0.25mL propylene glycol in this volumetric flask, this volumetric flask adds to about 90% volume with glycerol formal.Then this volumetric flask is placed on the electromagnetic shaker, and about 30 minutes of ultrasonic once in a while jolting, clear solutions obtained.Then this volumetric flask is added to the 5mL volume with glycerol formal.When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
The solution that also prepares free flunixin (promptly not being salt) by the following method: weighing 1.5g flunixin, place the 10mL volumetric flask, volumetric flask adds to about 90% volume with N-Methyl pyrrolidone.Then this volumetric flask is placed on the electromagnetic shaker, and about 10 minutes of ultrasonic once in a while jolting, clear solutions obtained.Then this volumetric flask is added to the volume of 10mL with N-Methyl pyrrolidone.When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
Flunixin is release in vitro from the Pharmaceutical composition that contains flunixin: the 1mL aliquot of above-mentioned each flunixin compositions is sealed in (can be from Pierce Biotechnology in the bag filter, Inc.of Rockford IL has bought), and this bag filter is suspended in the flask that contains 150mL pH 7.4 phosphate buffered saline(PBS).When bag filter is suspended in the flask that contains phosphate buffered saline(PBS), observes in this bag filter and formed precipitation.Take out the solution of the buffer salt solution of aliquot then at each interval, and measure the concentration of flunixin with high performance liquid chromatography (HPLC).
Analyze for HPLC, 100 μ L are injected into Phenomenex Luna 5:M phenyl-hexyl 100A, 250 * 4.6mm analytical column, flow velocity 1.7mL/min.This HPLC is connected with the UV detector, detects wavelength 285nm.HPLC post basis is used the gradient eluent eluting with lower curve:
Time pump A% pump B%
0 30 70
10.5 85 15
Wherein the solvent among the pump A is the 25mM phosphate buffer of pH 2.4, and the solvent among the pump B is an acetonitrile.Total run time is 25 minutes.Then, by comparing standard curve peak area, measure the serum-concentration of flunixin corresponding to the HPLC peak area under curve and the known flunixin phosphate buffered saline(PBS) concentration of flunixin.Standard curve is with the preparation of the flunixin of following concentration: 4,2,1,0.5 and 0g/mL.
Fig. 1 represents the function of the flunixin percentage comparison time that each flunixin preparation is discharged.(▲) represents the flunixin percentage ratio that discharges from the compositions of the salt that contains flunixin and tryptophan monooctyl ester, the flunixin percentage ratio that (■) the flunixin percentage ratio that discharges from the compositions of the salt that contains flunixin and tryptophan butyl ester of representative, and (◆) representative discharges from contain the compositions that is dissolved in free flunixin the N-Methyl pyrrolidone.
The result who describes among Fig. 1 shows that flunixin compositions of the present invention with than the obvious slower speed of the compositions that contains free flunixin, is discharged into flunixin in the normal saline.These results also prove by changing amino-acid ester, the rate of release of scalable flunixin.The data show flunixin of describing among Fig. 1 release ratio from the tryptophan monooctyl ester discharges slower from the tryptophan butyl ester.The lipophile of tryptophan monooctyl ester is stronger than tryptophan butyl ester.
The flunixin administration of embodiment 6.3 dogs
With the dosage of 8mg/kg, inject commercially available flunixin (Banamine for two dogs
, Schering-Plough Animal Health, Omaha, NE sells).
With the dosage of 8mg/kg, contain embodiment 9.2 compositionss of the propylene glycol and the glycerol formal solution of flunixin and tryptophan monooctyl ester salt for four dog injections.
At each interval, extract the blood of every dog, and according to the serum-concentration of following program determination flunixin:
(i) by with 1mL methanol and 1mL deionized water, adopt gravity flow to wash pretreatment Strata X-C33 μ m cation mixed type polymer 30mg/mL post;
(ii) 1mL is joined in this pretreated post with the acidifying serum of 20 μ l phosphoric acid;
(iii) post 1mL 0.1%H
3PO
4/ H
2O, 1mL acetonitrile and 2mL methanol wash;
(iv) post is with 4mL ammonia hydroxide/methanol (15%2M NH
4OH/ methanol) eluting;
(v) use nitrogen current, solvent is removed from eluent; And
(vi) then, residue obtained phosphate buffer with 50: 50 methanol/50mM pH 2.3 of 1mL dissolves again, and analyzes through HPLC with the HPLC method of describing among the embodiment 9.2.
Fig. 2 represents that two give Banamine
The average flunixin serum-concentration of dog to the function of time.
Fig. 3 represents that four give the function of the average flunixin serum-concentration of embodiment 9.2 compositions dogs to the time, and said composition contains the propylene glycol and the glycerol formal solution of flunixin and tryptophan monooctyl ester salt.
The result who describes among Fig. 2 and Fig. 3 shows the compositions of the application of the invention, than using commercially available flunixin preparation (Banamine
, Schering-Plough Animal Health, Omaha, NE sells) and to keep the longer time of the effective serum levels of flunixin be possible.
The preparation of embodiment 6.4N-acylamino acid
Phenylalanine butyramide: the 5g phenylalanine is joined in the 20mL butyryl oxide., and the gained mixture was heated about 3 hours in about 100 ℃.Excessive butyryl oxide. is removed in decompression then, obtains solid residue, and this solid residue ethyl alcohol recrystallization obtains the phenylalanine butyramide.
Embodiment 6.5 comprises the compositions of phosphorylated nucleotide
Single adenosine phosphate (AMP) is as the model of phosphorylated nucleotide.
The compositions that contains the salt of AMP and isoleucine butyl ester: weighing 1.2g isoleucine butyl ester and 1g AMP place the 10mL volumetric flask, and add to about 90% volume of volumetric flask with glycerol formal.This volumetric flask of jolting makes AMP isoleucine butyl ester dissolving, fills it up with volume to volumetric flask with glycerol formal then.Available 1 equivalent phosphorylated nucleotide for example adefovirdipivoxil replaces whenever amount AMP.1g AMP promptly in the presence of no isoleucine butyl ester, will not dissolve in the 10mL glycerol formal separately.
The compositions that contains the salt of the salt of AMP and isoleucine butyl ester and capric acid and isoleucine butyl ester: weighing 1g AMP, 0.99g capric acid, 2.4g isoleucine butyl ester, place the 10mL volumetric flask, and add to about 90% volume of volumetric flask with glycerol formal.This volumetric flask of jolting makes the dissolving of AMP, capric acid and isoleucine butyl ester, fills it up with volume to volumetric flask with glycerol formal then.1 equivalent phosphorylated nucleotide for example adefovirdipivoxil can replace whenever amount AMP.
The compositions that contains the salt of AMP and tyrosine butyl ester: weighing 0.682g tyrosine butyl ester and 0.5g AMP place the 10mL volumetric flask, and add to about 90% volume of volumetric flask with N-Methyl pyrrolidone.About 30 minutes of ultrasonic this volumetric flask makes the dissolving of AMP and tyrosine butyl ester, fills it up with volume to volumetric flask with N-Methyl pyrrolidone then.1 equivalent phosphorylated nucleotide for example adefovirdipivoxil can replace whenever amount AMP.0.5g AMP promptly in the presence of no tyrosine butyl ester, will not dissolve in the 10mL N-Methyl pyrrolidone separately.
The compositions that contains the salt of AMP and phenylalanine dodecyl ester: weighing 1g phenylalanine dodecyl ester and 0.347g AMP place the 10mL volumetric flask, and add to about 90% volume of volumetric flask with N-Methyl pyrrolidone.About 30 minutes of ultrasonic this volumetric flask suspends AMP and phenylalanine dodecyl ester, fills it up with volume to volumetric flask with N-Methyl pyrrolidone then.This volumetric flask of jolting then obtains the composition for injection of AMP and phenylalanine dodecyl ester suspension.1 equivalent phosphorylated nucleotide for example adefovirdipivoxil can replace whenever amount AMP.
Contain AMP and 2.1 equivalents by lysine and C
16Straight chain alcohol (is CH
3(CH
2)
14CH
2-OH) the compositions of salt of preparation ester: 45mg AMP and 96mg lysine ester are suspended in about 2mL glycerol formal.The gained suspension is placed ultra sonic bath, and vibrations obtain settled solution.The volume of this solution is made the 3mL volume.Gained solution contains the AMP salt that concentration is about 1.5% (w/v).When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
Contain AMP and 2.1 equivalents by lysine and C
16Straight chain alcohol (is CH
3(CH
2)
14CH
2-OH) the compositions of salt of preparation ester: 150mg AMP and 320mg lysine ester are suspended in about 2mL glycerol formal.The gained suspension is placed ultra sonic bath, and vibrations obtain settled solution.The volume of this solution is made the 3mL volume.Gained solution contains the AMP salt that concentration is about 5% (w/v).When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
Contain AMP and 6.6 equivalents by lysine and C
16Straight chain alcohol (is CH
3(CH
2)
14CH
2-OH) the compositions of salt of preparation ester: 150mg AMP and 1.92g lysine ester are suspended in about 2mL glycerol formal.The gained suspension is placed ultra sonic bath, and vibrations obtain settled solution.The volume of this solution is made the 3mL volume.Gained solution contains the AMP salt that concentration is about 5% (w/v).When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
Embodiment 6.6: comprise isoleucine butyl ester, lauric acid and terbinafine
Pharmaceutical composition
A: in the 25mL volumetric flask, terbinafine (5g), lauric acid (7.56g) and isoleucine butyl ester (3.54g) are suspended in about 15mL glycerol formal.Then with the ultrasonic settled solution that obtains of gained suspension.Add propylene glycol (1.5mL), and gained solution is fully mixed.Then this volumetric flask is added to the 25mL volume with glycerol formal, obtain clear solutions.The gained Pharmaceutical composition contains 20% (w/v) terbinafine laruate.This Pharmaceutical composition also contains the salt that forms between lauric acid and the isoleucine butyl ester.When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
B: prepare another kind of Pharmaceutical composition as a comparison, said composition does not comprise the salt that forms between lauric acid and the isoleucine butyl ester.Said composition is prepared as follows: in the 25mL volumetric flask, terbinafine (5g), lauric acid (1.1 equivalent) are suspended in about 15mL glycerol formal, and ultrasonic gained suspension obtains settled solution.Add propylene glycol (1.5mL), and gained solution is fully mixed.Then this volumetric flask is added to the 25mL volume with glycerol formal, obtain clear solutions.The gained Pharmaceutical composition contains 20% (w/v) terbinafine laruate.When being injected into this Pharmaceutical composition of 1mL in the 5mL water, observing and form precipitation.
Embodiment 6.7: the terbinafine administration of dog
With the dosage of 20mg/kg, give the Pharmaceutical composition of three dogs (dog A, B and C) embodiment 9.6A by the cervical region subcutaneous injection.
With the dosage of 20mg/kg, give the Pharmaceutical composition of three other dogs (dog D, E and F) embodiment 9.6B by the cervical region subcutaneous injection.
Three other dogs (dog G, H and I) per os gives commercially available 250mg terbinafine sheet (with Lamisil Tablets
, sell by Novartis Pharmaceutical Corporation of NewJersey), once a day, continuous 6 days.
In 0,1,12,24,48,72 and 168 hour, collect the blood serum sample of every dog, and carry out Solid-Phase Extraction as described below, analyze through HPLC with HPLC method as described below then.Equally, injected back 7 days, every dog carries out the Skin biopsy of the right side, a left side and the central part in omoplate dorsal part zone, for organizing as described below of terbinafine analysis.Give the dog of terbinafine for injection, monitor the untoward reaction of injection site by the veterinary.
Tissue preparation:
1. thoroughly chopping is organized.
2. will be about the tissue of 5mg chopping place bottle, and add 10mL methanol.
3. 200 μ L phosphoric acid are joined in the gained methanol solution.
4. cool off this methanol solution in ice bath, making is heated minimizes, and makes this methanol solution homogenize then about 1 minute.
5. about 20 seconds of ultrasonic this methanol solution.
6. this methanol solution of homogenize is about 1 minute.
7. about 20 seconds of ultrasonic this methanol solution.
8. in about 4 ℃, with about 8250rcf with centrifugal about 30 minutes of this methanol solution.
9. the gained supernatant is decanted in the other bottle, to avoid during Solid-Phase Extraction the granular substance back-mixing in supernatant.
10. by following description supernatant is carried out Solid-Phase Extraction.
The Solid-Phase Extraction of serum or supernatant:
1. with 1mL methanol and 2mL deionized water, adopt gravity flow pretreatment Strata30mg/1mL X-C post (by Mallinckrodt Baker, Inc.of Phillipsburg, NJ sale).
2. 1mL is joined in this pretreated post with the 20 acidifying serum of μ L phosphoric acid (or supernatant).
3. use 1mL 0.1%H
3PO
4/ H
2O, 1mL acetonitrile and this post of 1mL methanol wash.
4. the methanol solution of this post with 1850 μ L, 15% diethylamine is eluted in the 2mL volumetric flask.
5. 15% diethylamine is added to volumetric flask to 2mL.
6. 1000 μ L, 50% phosphoric acid is joined in this 2mL volumetric flask, and vortex gained mixture.
7. gained solution is filled in the bottle.
8. with HPLC method as described below, analyze the terbinafine in the gained solution.
The HPLC of terbinafine analyzes:
Post: Phenomenex Luna
5 μ, C8,100 , 250mm * 4.6mm (by Phenomenex of Torrance, CA sells)
Mobile phase: 40%25mM pH 2.4 phosphate buffers, 60% methanol
Eluting feature: isocratic elution
Detect: UV, 223nm
Temperature: room temperature
Injection: 100 μ L
Running time: 20 minutes, degree of grade
Flow velocity: 1mL/min
Detectability: about 8ng/mL
Quantitative limit: about 75ng/mL
By comparing standard curve peak area, measure the concentration of terbinafine corresponding to the HPLC peak area under curve and the known terbinafine concentration of terbinafine.Standard curve obtains by following steps:
1. by weighing 100mg terbinafine, place the 100mL volumetric flask and be diluted to volume, preparation concentration is the methanol standard stock solution of the terbinafine of 1mg/mL.
2. prepare following serum admixture solution:
Solution A: 400 μ L standard stock solution+600 μ L methanol=400 μ g/mL terbinafines
Solution B: 200 μ L standard stock solution+800 μ L methanol=200 μ g/mL terbinafines
Solution C: 100 μ L standard stock solution+900 μ L methanol=100 μ g/mL terbinafines
Solution D: 50 μ L standard stock solution+950 μ L methanol=50 μ g/mL terbinafines
Solution E: 10 μ L standard stock solution+990 μ L methanol=10 μ g/mL terbinafines
Solution F:0 μ L standard stock solution+1000 μ L methanol=0 μ g/mL terbinafine
3. prepare following standard serum solution:
A.15 μ L solution A+1485 μ L serum=4 μ g/mL terbinafines
B.15 μ L solution B+1485 μ L serum=2 μ g/mL terbinafines
C.15 μ L solution C+1485 μ L serum=1 μ g/mL terbinafine
D.15 μ L solution D+1485 μ L serum=0.5 μ g/mL terbinafine
E.15 μ L solution E+1485 μ L serum=0.1 μ g/mL terbinafine
F.15 μ L solution E+1485 μ L serum=0 μ g/mL terbinafine
With above-mentioned each the standard serum solution of above-mentioned HPLC methods analyst, obtain standard curve.
The peak area of each standard serum solution gained is as follows:
| Terbinafine concentration (μ g/mL) | The HPLC area |
| 0.1 | 59.92624 |
| 0.5 | 279.6904 |
| 1.0 | 566.0115 |
| 2.0 | 1073.03 |
| 4.0 | 2214.295 |
The methanol solution of 1mL 15% diethylamine is joined the 2mL volumetric flask, then add 10 μ L solution A, and fill it up with volumetric flask to volume, preparation positive control (can detect terbinafine) in order to prove this analysis with the methanol solution of 15% diethylamine.In gained solution, add 1mL 50% phosphoric acid then, and with turbine mixer mixing gained solution.The terbinafine concentration of gained positive control is 4 μ g/mL.Except using 10 μ L solution D, concentration is that the positive control of 0.5 μ g/mL can be according to identical method preparation.
The methanol solution of 2mL 15% diethylamine is mixed in test tube with 1mL 50% phosphoric acid, and gained solution was mixed about 10 seconds, preparation negative control (not having other chemical compounds and terbinafine co-elute) in order to prove with turbine mixer.
Each terbinafine mean concentration of organizing in the dog serum is measured as stated above, is listed in down Table I:
Table I:
| The average serum concentration of terbinafine | |||
| Time (hour) | Dog A, B and C | Dog D, E and F | Dog G, H and I |
| 0 | 0.00 | 0.00 | 0.00 |
| 1 | 0.02 | 0.01 | 2.36 |
| 12 | 0.12 | 0.02 | 0.08 |
| 24 | 0.27 | 0.02 | 0.46 |
| 48 | 0.05 | 0.02 | 0.25 |
| 72 | 0.17 | 0.01 | 0.85 |
| 168 | 0.05 | 0.12 | 3.23 |
It is known that terbinafine may toxigenicity under high whole body and tissue concentration.The result is presented at that single injection gives Pharmaceutical composition of the present invention in time of 7 days, and the terbinafine serum levels of generation is littler than the commercially available terbinafine tablet of orally give once a day., Pharmaceutical composition of the present invention provides on the physiology and the relevant terbinafine serum levels of expection therapeutical effect.
The Pharmaceutical composition of the present invention that contains the salt that forms between terbinafine laruate and lauric acid and the isoleucine butyl ester provides lower terbinafine serum levels than continuous 6 days once a day oral 250mg terbinafine sheets.Therefore, giving terbinafine with Pharmaceutical composition of the present invention, to give terbinafine toxicity than per os littler.
The veterinary gives the dog of terbinafine with each injection of eye examination, it is the injection site of dog A, B and C and dog D, E and F, the result shows the dog (being dog A, B and C) that contains the terbinafine laruate and also contain the embodiment 9.6A Pharmaceutical composition of the salt that forms between lauric acid and the isoleucine butyl ester, than the dog (being dog D, E and F) of the embodiment 9.6B Pharmaceutical composition that contains the terbinafine laruate, in injection site demonstration swelling and stimulation still less.These results show the Pharmaceutical composition that contains the salt that forms between lauric acid and the isoleucine butyl ester, with the combination of terbinafine laruate, than the Pharmaceutical composition that only contains terbinafine laruate generation stimulation still less when the subcutaneous injection administration.
Also measured the terbinafine tissue concentration of each dog, be listed in down in the Table II.
Table II
| Dog | Terbinafine tissue concentration (μ g/g) in the right side, a left side and the central part gained tissue in omoplate dorsal part zone | ||
| Central authorities | A left side | Right | |
| A | 31.34 | -- | 222.5 a |
| B | 19.74 | 27.43 | 38.40 |
| C | 20.17 | 15.38 | 28.14 |
| On average | 24.72 | 21.40 | 96.36(33.27) b |
| D | 29.54 | 26.64 | 20.08 |
| E | 16.42 | 19.26 | 141.61 |
| F | 45.43 | 31.48 | 34.82 |
| On average | 30.49 | 25.79 | 65.50 |
| G | 97.24 | 117.52 | 108.23 |
| H | 121.57 | 73.68 | 72.80 |
| I | 46.79 | 33.47 | 38.11 |
| On average | 88.53 | 74.89 | 73.05 |
aNumerical value obviously has error, though the source of error is unclear.
bIf get rid of the value of the 222.5 μ g/g of dog A, then meansigma methods is 33.27 μ g/g.
As discussed above, known terbinafine may toxigenicity under high whole body and tissue concentration.The result is presented at that single injection gives Pharmaceutical composition of the present invention in time of 7 days, and more oral commercially available terbinafine tablet is little than once a day for the terbinafine tissue concentration of generation., Pharmaceutical composition of the present invention provides on the physiology the relevant terbinafine tissue concentration of therapeutical effect with expection.
The invention is not restricted to the scope of disclosed specific embodiments among the embodiment, these embodiment are as the example of some aspects of the present invention, and any embodiment that is equal on the function also within the scope of the invention.Really, except that shown in herein and described those, various modifications of the present invention will show that to those skilled in the art easily to be seen, and will fall within the scope of the claims.
Quoted many lists of references, its whole disclosure is attached to herein by reference.
Claims (50)
1. Pharmaceutical composition, described compositions comprises (i) amino-acid ester or amino acid amide; (ii) acidic drug reactive compound, and (iii) pharmaceutically acceptable organic solvent; Described Pharmaceutical composition is injectable and forms precipitation when the injection entry.
2. the Pharmaceutical composition of claim 1, wherein said amino-acid ester or amino acid amide are for being selected from following amino acid whose ester or amide: glycine, alanine, valine, leucine, isoleucine, phenylalanine, agedoite, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine.
3. the Pharmaceutical composition of claim 1, wherein said amino-acid ester is by with aminoacid and straight or branched, the saturated or pure esterification acquisition of unsaturated alkyl.
4. the Pharmaceutical composition of claim 1, wherein said alkylol is C
1-C
22Alcohol.
5. the Pharmaceutical composition of claim 4, wherein C
1-C
22Alcohol is selected from methanol; Ethanol; Propanol; Butanols; Amylalcohol; Hexanol; Enanthol; Capryl alcohol; Nonyl alcohol; Decanol; Tip-nip; Dodecanol; Tridecyl alcohol; Tetradecanol; Pentadecanol; Hexadecanol; Heptadecanol; Octadecanol; 1-propenol-3; Cyclopentanol; Hexalin; Suitable-9-hexadecylene alcohol; Suitable-the 9-oleic alcohol; Suitable, suitable-9,12-18 dienols and suitable, suitable, suitable-9,12,15-18 enols.
6. the Pharmaceutical composition of claim 1, wherein said acidic drug reactive compound is selected from aspirin, flunixin, diclofenac, naproxen, ketoprofen, carprofen and ibuprofen.
7. the Pharmaceutical composition of claim 1, wherein said acidic drug reactive compound is a phosphorylated nucleotide.
8. the Pharmaceutical composition of claim 7, wherein said nucleotide is adefovirdipivoxil.
9. the Pharmaceutical composition of claim 1, wherein said solvent is selected from ketopyrrolidine, N-N-methyl-2-2-pyrrolidone N-, Polyethylene Glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraethylene glycol (TEG), tetrahydrofurfuryl alcohol, glyceryl triacetate, Allyl carbonate, dimethyl acetylamide, dimethyl formamide, dimethyl sulfoxide and combination thereof.
10. the Pharmaceutical composition of claim 1, the molar ratio of acidic-group and described amino-acid ester is about 1.5 on the wherein said acidic drug reactive compound: 1-1: in 1 the scope.
11. the Pharmaceutical composition of claim 1, the molar ratio of acidic-group and described amino-acid ester is about 1: 1 on the wherein said acidic drug reactive compound.
12. the Pharmaceutical composition of claim 1, the total amount of wherein said acidic drug reactive compound and described amino-acid ester account for the about 1-90% weight of described Pharmaceutical composition.
13. the Pharmaceutical composition of claim 1, the total amount of wherein said acidic drug reactive compound and described amino-acid ester account for the about 10-60% weight of described Pharmaceutical composition.
14. the Pharmaceutical composition of claim 1, wherein said pharmaceutical active compounds are flunixin, and described amino-acid ester is tryptophan monooctyl ester or tryptophan butyl ester.
15. the Pharmaceutical composition of claim 1, the glycerol formal solution that wherein said pharmaceutically acceptable organic solvent is about 5% propylene glycol.
16. a Pharmaceutical composition, described compositions comprises (i) amino-acid ester or amino acid amide; (ii) carboxylic acid; The pharmaceutically acceptable salt of (iii) neutral pharmaceutical active compounds or pharmaceutical active compounds; And (iv) pharmaceutically acceptable organic solvent; Described Pharmaceutical composition is injectable and forms precipitation when the injection entry.
17. the Pharmaceutical composition of claim 16, wherein said amino-acid ester or amino acid amide are for being selected from following amino acid whose ester or amide: glycine, alanine, valine, leucine, isoleucine, phenylalanine, agedoite, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine.
18. the Pharmaceutical composition of claim 16, wherein said amino-acid ester is by with aminoacid and straight or branched, the saturated or pure esterification acquisition of unsaturated alkyl.
19. the Pharmaceutical composition of claim 18, wherein said alkylol are C
1-C
22Alcohol.
20. the Pharmaceutical composition of claim 19, wherein C
1-C
22Alcohol is selected from: methanol; Ethanol; Propanol; Butanols; Amylalcohol; Hexanol; Enanthol; Capryl alcohol; Nonyl alcohol; Decanol; Tip-nip; Dodecanol; Tridecyl alcohol; Tetradecanol; Pentadecanol; Hexadecanol; Heptadecanol; Octadecanol; 1-propenol-3; Cyclopentanol; Hexalin; Suitable-9-hexadecylene alcohol; Suitable-the 9-oleic alcohol; Suitable, suitable-9,12-18 dienols and suitable, suitable, suitable-9,12,15-18 enols.
21. the Pharmaceutical composition of claim 16, wherein said carboxylic acid are C
1-C
22Carboxylic acid.
22. the Pharmaceutical composition of claim 21, wherein said carboxylic acid are C
6-C
18Carboxylic acid.
23. the Pharmaceutical composition of claim 21, wherein said carboxylic acid is selected from acetic acid, propanoic acid, butanoic acid, valeric acid, caproic acid, benzoic acid, caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, palmitic acid, oleic acid, linoleic acid plus linolenic acid.
24. the Pharmaceutical composition of claim 16, wherein said carboxylic acid are the N-acylated amino with following general formula:
Wherein:
R is for can choose substituted straight chain or cyclic hydrocarbon group, aryl or aromatics or non-aromatic heterocyclic group wantonly; And
R
2Be formula-C (O)-R
5Acyl group, R wherein
3Be the C that replaces
1-C
21Alkyl.
25. the Pharmaceutical composition of claim 24, wherein R
5Be C
5-C
21Alkyl.
26. the Pharmaceutical composition of claim 24, wherein R
2For being selected from following acyl group: acetyl group, propiono, bytyry, caproyl, caproyl, heptanoyl group, caprylyl, pelargonyl group, capryl, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecane acyl group, octadecanoyl, lauroyl, myristoyl, palmityl, stearyl, palmitoleoyl, oleoyl, inferior oleoyl, Caulis et Folium Lini acyl group and benzoyl.
27. the Pharmaceutical composition of claim 16, wherein said solvent are selected from ketopyrrolidine, N-N-methyl-2-2-pyrrolidone N-, Polyethylene Glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraethylene glycol (TEG), tetrahydrofurfuryl alcohol, glyceryl triacetate, Allyl carbonate, dimethyl acetylamide, dimethyl formamide, dimethyl sulfoxide and combination thereof.
28. the Pharmaceutical composition of claim 16, wherein said pharmaceutical active compounds are neutral pharmaceutical active compounds.
29. the Pharmaceutical composition of claim 28, wherein said carboxylic acid are C
1-C
22Carboxylic acid.
30. the Pharmaceutical composition of claim 29, wherein said carboxylic acid are C
6-C
18Carboxylic acid.
31. the Pharmaceutical composition of claim 28, the amount that wherein said neutral pharmaceutical active compounds exists accounts for the about 1-90% weight of described Pharmaceutical composition.
32. the Pharmaceutical composition of claim 28, wherein said amino-acid ester and the total amount of described carboxylic acid in described Pharmaceutical composition account for the about 2-50% weight of described Pharmaceutical composition.
33. the Pharmaceutical composition of claim 16, wherein said pharmaceutical active compounds are the salt that acidic drug reactive compound and amino-acid ester form.
34. the Pharmaceutical composition of claim 33, wherein said carboxylic acid are C
1-C
22Carboxylic acid.
35. the Pharmaceutical composition of claim 34, wherein said carboxylic acid are C
6-C
18Carboxylic acid.
36. the Pharmaceutical composition of claim 31, the amount that the salt that wherein said acidic drug reactive compound and amino-acid ester or amino acid amide form exists accounts for the about 1-90% weight of described Pharmaceutical composition.
37. the Pharmaceutical composition of claim 33, the total amount of wherein said carboxylic acid and described amino-acid ester or amino acid amide account for the about 2-50% weight of described Pharmaceutical composition.
38. a Pharmaceutical composition, described compositions comprises:
(i) the N-acylated amino ester of following general formula:
Wherein:
R is for can choose substituted straight chain or cyclic hydrocarbon group, aryl or aromatics or non-aromatic heterocyclic group wantonly; And
R
2Be formula-C (O)-R
5Acyl group, R wherein
3Be the C that replaces
1-C
21Alkyl;
(ii) alkalescent medicine reactive compound; And
(iii) pharmaceutically acceptable organic solvent;
Described Pharmaceutical composition is injectable and forms precipitation when the injection entry.
39. the Pharmaceutical composition of claim 38, wherein said N-acylamino acid is for being selected from following amino acid whose N-acylamino acid: glycine, alanine, valine, leucine, isoleucine, phenylalanine, agedoite, glutamine, tryptophan, proline, serine, threonine, tyrosine, hydroxyproline, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine.
40. the Pharmaceutical composition of claim 38 wherein is C
5-C
21Alkyl.
41. the Pharmaceutical composition of claim 38, wherein said C
5-C
21Alkyl select oneself acyl group, lauroyl, myristoyl, palmityl, stearyl, palmitoleoyl, oleoyl, inferior oleoyl and Caulis et Folium Lini acyl group.
42. the Pharmaceutical composition of claim 38, wherein said alkalescent medicine reactive compound is selected from penicillin, streptomycin, azithromycin, Roxithromycin, tilmicosin, oxytetracycline and doxycycline.
43. the Pharmaceutical composition of claim 38, wherein said solvent are selected from ketopyrrolidine, N-N-methyl-2-2-pyrrolidone N-, Polyethylene Glycol, propylene glycol, glycerol formal, isosorbide dimethyl ether, ethanol, dimethyl sulfoxide, tetraethylene glycol (TEG), tetrahydrofurfuryl alcohol, glyceryl triacetate, Allyl carbonate, dimethyl acetylamide, dimethyl formamide, dimethyl sulfoxide and combination thereof.
44. the Pharmaceutical composition of claim 38, the molar ratio of basic group and described N-acylamino acid is about 1.5 on the wherein said alkalescent medicine reactive compound: 1-1: in 1 the scope.
45. the Pharmaceutical composition of claim 38, the molar ratio of basic group and described N-acylamino acid is about 1: 1 on the wherein said alkalescent medicine reactive compound.
46. the Pharmaceutical composition of claim 38, the total amount of wherein said alkalescent medicine reactive compound and described N-acylamino acid account for the about 1-90% weight of described Pharmaceutical composition.
47. the Pharmaceutical composition of claim 38, the total amount of wherein said alkalescent medicine reactive compound and described N-acylamino acid account for the about 10-60% weight of described Pharmaceutical composition.
48. the method for the treatment of or preventing the animal disease, described method comprises through injection has the animal right of needs to require 1 Pharmaceutical composition.
49. the method for the treatment of or preventing the animal disease, described method comprises through injection has the animal right of needs to require 16 Pharmaceutical composition.
50. the method for the treatment of or preventing the animal disease, described method comprises through injection has the animal right of needs to require 38 Pharmaceutical composition.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62268904P | 2004-10-28 | 2004-10-28 | |
| US60/622,689 | 2004-10-28 | ||
| US63817804P | 2004-12-23 | 2004-12-23 | |
| US60/638,178 | 2004-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101048139A true CN101048139A (en) | 2007-10-03 |
Family
ID=36319633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800366905A Pending CN101048139A (en) | 2004-10-28 | 2005-10-27 | Compositions for controlled delivery of pharmaceutically active compounds |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US8293253B2 (en) |
| EP (1) | EP1804771A2 (en) |
| JP (1) | JP5144267B2 (en) |
| CN (1) | CN101048139A (en) |
| AU (1) | AU2005302554A1 (en) |
| CA (1) | CA2580363A1 (en) |
| WO (1) | WO2006050002A2 (en) |
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| CN102861374A (en) * | 2011-07-08 | 2013-01-09 | 上海市计划生育科学研究所 | Pessulum capable of steadily releasing medicine |
| CN104955472A (en) * | 2012-10-17 | 2015-09-30 | 诺和诺德保健股份有限公司 | Fatty acid acylated amino acids for growth hormone delivery |
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| WO2008021367A2 (en) | 2006-08-11 | 2008-02-21 | President And Fellows Of Harvard College | Moenomycin biosynthesis-related compositions and methods of use thereof |
| US8828960B2 (en) * | 2007-07-17 | 2014-09-09 | Idexx Laboratories, Inc. | Amino acid vitamin ester compositions for controlled delivery of pharmaceutically active compounds |
| WO2009046314A2 (en) * | 2007-10-04 | 2009-04-09 | President And Fellows Of Harvard College | Moenomycin analogs, methods of synthesis, and uses thereof |
| US20110177157A1 (en) * | 2010-01-19 | 2011-07-21 | Idexx Laboratories, Inc. | Compositions for Controlled Delivery of Pharmaceutically Active Compounds |
| WO2011151786A2 (en) * | 2010-06-04 | 2011-12-08 | North-West University | Injectable formulation |
| CN105853393A (en) * | 2011-01-24 | 2016-08-17 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | Nanoparticles for drug percutaneous delivery and body delivery |
| FR2977585B1 (en) * | 2011-07-06 | 2015-08-28 | Ard Sa | PROCESS FOR PREPARING ESTERS |
| US9273084B2 (en) | 2012-04-06 | 2016-03-01 | President And Fellows Of Harvard College | Moenomycin analogs, methods of synthesis, and uses thereof |
| EP2850091A1 (en) | 2012-04-06 | 2015-03-25 | President and Fellows of Harvard College | Methods and compounds for identifying glycosyltransferase inhibitors |
| WO2013152279A1 (en) | 2012-04-06 | 2013-10-10 | President And Fellows Of Harvard College | Chemoenzymatic methods for synthesizing moenomycin analogs |
| JPWO2016121753A1 (en) * | 2015-01-27 | 2017-11-02 | 味の素株式会社 | Skin penetration control method |
| CN104667282B (en) * | 2015-02-09 | 2017-09-26 | 华北制药集团动物保健品有限责任公司 | A kind of compound oxytetracycline injection and preparation method |
| WO2022106253A1 (en) * | 2020-11-18 | 2022-05-27 | Dsm Ip Assets B.V. | New synthesis of l-phenylalanine butyramide |
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-
2005
- 2005-10-27 CA CA002580363A patent/CA2580363A1/en not_active Abandoned
- 2005-10-27 AU AU2005302554A patent/AU2005302554A1/en not_active Abandoned
- 2005-10-27 EP EP05814857A patent/EP1804771A2/en not_active Withdrawn
- 2005-10-27 WO PCT/US2005/038664 patent/WO2006050002A2/en active Application Filing
- 2005-10-27 JP JP2007539083A patent/JP5144267B2/en active Active
- 2005-10-27 CN CNA2005800366905A patent/CN101048139A/en active Pending
- 2005-10-27 US US11/259,027 patent/US8293253B2/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861374A (en) * | 2011-07-08 | 2013-01-09 | 上海市计划生育科学研究所 | Pessulum capable of steadily releasing medicine |
| CN102861374B (en) * | 2011-07-08 | 2014-06-25 | 上海市计划生育科学研究所 | Pessulum capable of steadily releasing medicine |
| CN104955472A (en) * | 2012-10-17 | 2015-09-30 | 诺和诺德保健股份有限公司 | Fatty acid acylated amino acids for growth hormone delivery |
Also Published As
| Publication number | Publication date |
|---|---|
| US20060093632A1 (en) | 2006-05-04 |
| US8293253B2 (en) | 2012-10-23 |
| JP5144267B2 (en) | 2013-02-13 |
| CA2580363A1 (en) | 2006-05-11 |
| EP1804771A2 (en) | 2007-07-11 |
| AU2005302554A1 (en) | 2006-05-11 |
| WO2006050002A2 (en) | 2006-05-11 |
| JP2008518916A (en) | 2008-06-05 |
| WO2006050002A3 (en) | 2006-12-21 |
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